152 results on '"Ligands"'
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2. Synthesis of Novel Chiral Phenanthroline Ligands and a Copper Complex.
- Author
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Tang, Jingjing, Li, Jian, Yang, Xueyan, and Zhang, Zhipeng
- Abstract
A novel class of chiral multidentate ligands has been designed and synthesized from the important classic ligand 1,10-phenanthroline and amino acids. The ligands were proven to be able to coordinate with copper(2+) ion by the formation of a novel chiral copper complex, the structure of which was determined by single-crystal X-ray diffraction. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
3. Synthese und Charakterisierung unterschiedlicher N,P-Ligandensysteme und deren Metallkomplexe sowie die Untersuchung ihrer photophysikalischen Eigenschaften
- Author
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Zovko, Christina and Zovko, Christina
- Subjects
- Ligands
- Abstract
Diese Dissertation beschreibt u.a. die Synthese und Charakterisierung neuartiger P,N-Ligandensysteme sowie deren Metallkomplexe, wobei ein besonderer Fokus auf den photophysikalischen Eigenschaften der Komplexe lag. Hierfür wurden drei unterschiedliche bifunktionelle Ligandensysteme, welche sowohl Stickstoff- als auch Phosphan bzw. Phosphansulfid-Funktionalitäten besitzen, synthetisiert. Als neuartige Liganden wurden ein Triarylphosphan-funktionalisiertes ß-Diketimin (PNac-H), ein Phosphan-funktionalisierter Amidin-Ligand (DPPM-C(N-Dipp)2H) sowie ein Phosphan- bzw. Phosphansulfid-funktionalisiertes BIAN-Ligandensystem ((S)PPh2-BIAN) realisiert. Aufgrund der unterschiedlichen Donorstellen (harte Stickstoff- und weiche Phosphan-Einheiten) der entsprechenden Liganden konnten mittels Metallkoordination unterschiedliche Koordinationspolyeder aufgebaut sowie selektive Metallkoordinationen realisiert werden. Die dargestellten P,N-Systeme erwiesen sich demnach als geeignete, multifunktionale Liganden zum Aufbau von mono- und bimetallischen Komplexen. Die spezifische Struktur des PNac-Ligandensystems ermöglichte u.a. die Stabilisierung einer reaktiven, subvalenten Ni(I)-Spezies, welche nachfolgend hinsichtlich ihrer Reaktivität und der Aktivierung kleiner Moleküle untersucht wurde. Für ausgewählte Metallkomplexe wurden zudem deren photophysikalischen Eigenschaften näher betrachtet.
- Published
- 2022
4. Zerovalent Metallosupramolecular Polymers as Precursors to Nanocomposites
- Author
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Stephen Schrettl, Luis M. Olaechea, and Christoph Weder
- Subjects
Composites ,Ligands ,Nanoparticles ,Platinum ,Polymers ,Chemistry ,QD1-999 - Published
- 2020
- Full Text
- View/download PDF
5. Photochemistry of Rhenium(i) Diimine Tricarbonyl Complexes in Biological Applications
- Author
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Kevin Schindler and Fabio Zobi
- Subjects
photochemistry ,Ligand ,Chemistry ,chemistry.chemical_element ,cellular probes ,General Medicine ,General Chemistry ,rhenium ,Rhenium ,Ligands ,Photochemistry ,photocorms ,Coordination Complexes ,Molecule ,photocatalysis ,QD1-999 ,Diimine - Abstract
Luminescent rhenium complexes continue to be the focus of growing scientific interest for catalytic, diagnostic and therapeutic applications, with emphasis on the development of their photophysical and photochemical properties. In this short review, we explore such properties with a focus on the biological applications of the molecules. We discuss the importance of the ligand choice to the contribution and their involvement towards the most significant electronic transitions of the metal species and what strategies are used to exploit the potential of the molecules in medicinal applications. We begin by detailing the photophysics of the molecules; we then describe the three most common photoreactions of rhenium complexes as photosensitizers in H2 production, photocatalysts in CO2 reduction and photochemical ligand substitution. In the last part, we describe their applications as luminescent cellular probes and how the photochemical ligand substitution is utilized in the development of photoactive carbon monoxide releasing molecules as anticancer and antimicrobial agents.
- Published
- 2021
6. [New tracers and combinations in radioligand therapy for prostate cancer].
- Author
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Tauber R, Lunger L, Eiber M, and Gschwend JE
- Subjects
- Male, Humans, Treatment Outcome, Prostate-Specific Antigen, Ligands, Radiopharmaceuticals adverse effects, Prostatic Neoplasms, Castration-Resistant radiotherapy
- Abstract
Background:
177 Lutetium radioligand therapy directed against the prostate-specific membrane antigen (PSMA) is a new approved option for the treatment of metastatic, castration-resistant prostate cancer associated with a favorable toxicity profile., Objectives: What are new or emerging developments in radioligand therapy for prostate cancer?, Materials and Methods: A review of the current literature was performed., Results: The further development of radioligand therapy for prostate cancer is currently taking place primarily in the following areas: application in earlier stages of the disease, use of alternative isotopes, development and use of new ligands, search for new target structures and combination with other forms of therapy., Conclusions: Radioligand therapy has become an integral part of the therapy algorithm in the treatment of metastatic, castration-resistant prostate cancer. Application in earlier stages of the disease is foreseeable. In the future, new ligands, alternative isotopes, new targets or combination therapies may increase efficacy and reduce toxicity., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)- Published
- 2023
- Full Text
- View/download PDF
7. [Oncological theranostics in nuclear medicine]
- Author
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Christina, Laschinsky, Ken, Herrmann, Wolfgang, Fendler, Michael, Nader, Harald, Lahner, Boris, Hadaschik, and Patrick, Sandach
- Subjects
Iodine Radioisotopes ,Male ,Positron Emission Tomography Computed Tomography ,Positron-Emission Tomography ,Humans ,Prostatic Neoplasms ,Nuclear Medicine ,Precision Medicine ,Radiopharmaceuticals ,Ligands ,Theranostic Nanomedicine - Abstract
The theranostic principle describes the diagnostic and therapeutic use of radioactive nuclides linked to biochemically active ligands. The oldest and most prominent field of application of theranostics in oncology is differentiated thyroid cancer treated by radioiodine therapy, which allows imaging of the iodine uptake and thus tumor manifestations by gamma (γ) radiation of radioiodine. Other areas of application include neuroendocrine tumors, castration-resistant prostate cancer and, in the context of individual therapeutic approaches, fibroblastic tumors. Imaging with beta-plus (βDas Prinzip der Theranostik beschreibt die sowohl diagnostische als auch therapeutische Nutzung radioaktiver Nuklide, geknüpft an biochemisch aktive Liganden. Das älteste und wohl bekannteste onkologische Einsatzgebiet der Theranostik ist das differenzierte Schilddrüsenkarzinom mit der Radiojodtherapie und der Möglichkeit, die Jodaufnahme und somit die Tumormanifestationen bildlich über die γ‑Strahlung des Radiojods darzustellen. Weitere Einsatzgebiete ergeben sich bei neuroendokrinen Tumoren, beim kastrationsresistenten Prostatakarzinom und individualtherapeutisch auch bei fibroblastischen Tumoren. Die Bildgebung erfolgt bei Verwendung von β
- Published
- 2022
8. [Role of innate receptors in chronic inflammation and autoimmunity]
- Author
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Marina, Babic and Chiara, Romagnani
- Subjects
Inflammation ,NK Cell Lectin-Like Receptor Subfamily K ,Toll-Like Receptors ,Cytokines ,Humans ,Autoimmunity ,Carrier Proteins ,Ligands - Abstract
Elucidating the basis of chronic disease courses and the development of appropriate treatment methods for inflammatory diseases still represent a big challenge for medical science, as the mechanisms driving aberrant immune reactions are mostly still unknown. Of particular interest is the identification of checkpoints that regulate the function and differentiation of proinflammatory cells during the pathogenesis, along with methods for modulation of specific checkpoints as a treatment approach. Innate receptors, such as members of the natural killer group 2 family (NKG2X), natural cytotoxicity receptors (NCR) or Toll-like receptors (TLRs), play an important role in modulating the immune response. NKG2 member D (NKG2D) is a potent activating receptor of the immune system, known as a sentinel for cellular danger signals presented by cells exposed to endoplasmic reticulum (ER) stress, cell death or an inflammatory cytokine milieu. NKG2A/C bind the non-classical HLA class I molecule, sense changes in ligand expression associated with malignant transformation and cellular stress and their main function is to send inhibitory or activating signals to NK cells and subsets of T cells. In this review, we present our latest knowledge on the understanding of the role of innate receptors in the context of chronic inflammation and autoimmunity with special emphasis on danger sensor receptors NKG2D and NKG2A/C.Die Aufklärung der Grundlagen chronischer Krankheitsverläufe und die Entwicklung geeigneter Behandlungsmethoden von Entzündungskrankheiten sind in der Biomedizin noch immer eine große Herausforderung. Die Mechanismen, die fehlgeleitete Immunreaktionen auslösen, sind größtenteils noch unbekannt. Von besonderem Interesse ist die Identifizierung von Kontrollpunkten oder Checkpoints, welche die Funktion und Differenzierung entzündungsfördernder Zellen während der Pathogenese regulieren, sowie von Methoden zur Modulation spezifischer Checkpoints als therapeutischen Ansatz. Angeborene Rezeptoren wie die Mitglieder der Natural-Killer-Group-2-Familie (NKG2X), natürliche Zytotoxizitätsrezeptoren (NCR) oder Toll-like-Rezeptoren (TLR) spielen eine wichtige Rolle bei der Modulation der Immunantwort. NKG2, Mitglied D (NKG2D) ist ein potenter Aktivierungsrezeptor des Immunsystems, der als Wächter für zelluläre Gefahrensignale bekannt ist, die von Zellen ausgehen, die einem Stress des endoplasmatischen Retikulums (ER), dem Zelltod oder einem entzündlichen Zytokinmilieu ausgesetzt sind. NKG2A/C binden das nichtklassische HLA-Klasse-I-Molekül, erkennen Veränderungen in der Ligandenexpression, die mit Transformation und Tumorzellstress einhergehen, und ihre Hauptfunktion besteht darin, hemmende bzw. aktivierende Signale an NK- und T‑Zellen zu senden. In dieser Übersichtsarbeit werden neue Erkenntnisse zum Verständnis der Rolle angeborener Rezeptoren bei chronischen Entzündungen und Autoimmunität mit besonderem Schwerpunkt auf dem Gefahrensensor-Rezeptor NKG2D und NKG2A/C präsentiert.
- Published
- 2021
9. Einfluss von Substituenten auf das Reaktionsverhalten und die elektrosterischen Eigenschaften von Carbodiphosphoranen
- Author
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Münzer, Jörn Eike and Kuzu, Istemi (Dr. rer. nat.)
- Subjects
metallorganische Chemie ,Carbone ,ligands ,carbodiphosphoranes ,Chemie ,carbones ,Komplexe ,complexes ,Carbodiphosphorane ,TEP ,ddc:540 ,Liganden ,Chemistry & allied sciences - Abstract
The results of this work are divided into four parts. The first part discusses the reactions between CDPs and hexamethyl disilazanide complexes. Both CDPPh and CDPcycl reacted with [Fe(HMDS)2] and the two complexes 1 and 2 (cf. Figure 1) were obtained and characterised. Compound 1 was synthesized by KNEUSELS and its molecular structure was obtained, but it was not fully characterised. In this work, further investigations were carried out with collaboration partners to clarify the magnetic properties and the bonding situation between the C0 atom and the Fe atom. The calculations show that the bond of C0 and the Fe atom is a double bond. With 2, another complex between a CDP and [Fe(HMDS)2] was obtained and its molecular structure could be obtained. No further investigations on the magnetic properties and nature of the C0-Fe bond have been carried. These would be of interest because they would allow good comparison to 1 in which the CDP ligand is not sterically fixed in its backbone. In addition, the first literature known CDP complexes with alkali metal cations could be obtained. By reacting group 1 HMDS complexes with a transition metal(II) HMDS complex and two equivalents of CDPs (CDPPh and CDPcycl), the complexes 3-6, as shown in Figure 2, were obtained. In these complexes, the group 1 cation is complexed by two CDP ligands. A closer look at the atomic distances, as well as the behaviour in solution, suggests that the interactions between the C0 atom and the alkali metal cations are rather weak covalent interactions or a mixture of covalent and electrostatic interactions. This assumption is supported by the large number of atomic distances within the VdW radii between the phenyl groups of the CDP ligands and the alkali metal cations. The resulting dispersion interactions indirectly weaken the bond between C0 and the alkali metal cation. This becomes obvious when comparing the CDPs. CDPPh has a greater alkali metal C0 atomic distance than CDPcycl complexes, but there are more contacts within the sum of the VdW radii in complexes 3 and 5 than in complexes 4 and 6. In order to be able to precisely determine the nature of the interactions between the CDPs and the alkali metal cation, quantum chemical calculations need to be carried out in the future so that the individual proportions of the different interactions can be quantified. The second part of this thesis dealt with the synthesis of new CDPs based on CDPCl. Here, the aim was to synthesize new CDPs via a metathesis reaction. A large number of substrates were tested for this purpose, but only limited success was achieved. It was possible to reproduce two literature known CDPs CDPNMe2 (8) and CDPNEt2, whereby the latter could only be characterised as a chloride salt in its protonated form (9) (cf. Figure 3). Although this has demonstrated that the reaction pathway pursued works, it does not provide the easy access to a large number of new CDPs that was hoped for. In consequence of this finding, this synthesis should not be pursued further for new CDPs. Other synthesis should be focused on in order to increase the number of CDPs. The third part of this work, again founded on the previous work from KNEUSELS, dealt with the reaction of CDPs with Group 15 compounds. KNEUSELS synthesised the compounds 10, 12 and 13 shown in Figure 4 and presented their molecular structure. For these compounds, the synthesis was optimised and the analysis was completed by extensive NMR studies. Furthermore, it was possible to obtain and completely characterise the CDPPh arsenic adduct 11 shown in Figure 5, which was previously unobtainable, thus completing the series of group 15 compounds of CDPPh. The reactivities of 10 and 13 were further investigated leading to the discovery of complex 14 shown in Figure 6. The complex exhibits an interesting dissociation behaviour in solution. First NMR studies suggest that the trifluoromethanesulfonate anions are free in solution. Based on the findings of KNEUSELS and the intramolecular electrophilic aromatic substitution discovered by KNEUSELS, the complex 16 as an analogue to 10 was presented with CDPcycl (cf. Figure 7). With 16, a similar reaction was attempted, unfortunately in vain, to react with an aromatic substrate in a intermolecular substitution reaction. Nevertheless, chloride substituents of 16 were systematically exchanged for phenyl groups and the compounds 17 and 18 shown in Figure 7 were obtained. Properties of complexes 16-18 were investigated by NMR analysis as well as DFT methods. The influence on the bond between CDPcycl and the P atom as the central atom could observed. The coupling constant of the 2JPP coupling decreases with decreasing electron density at the central P atom. In DFT calculations, a relative increase in the orbital coefficient at the C0 (HOMO) was observed with increasing electron density at the central phosphorus atom. Further investigations in this area should be aiming to understand the electrophilic aromatic substitution as a pathway to new complexes. The fourth part of this thesis dealt with the electrosteric characterization of CDPs. For this purpose the CDPcycl could be characterised electrosterically by the synthesis of the complexes shown in Figure 8 and compared to literature known CDPs. From these two complexes it was possible to determine the %Vbur and from complex 21 from TEP. As expected, the %Vbur of 39.9-41.7 % of CDPcycl is slightly smaller than for the CDPPh (41.9-43.4 %). With a TEP of 2024 cm-1 CDPcycl has the lowest TEP (highest total donor strength) of CDPs known so far. In general, electrosteric characterisation is a method that holds the potential to be used as a standard characterisation technique to classify new ligands. With the respective results, the ligands can be selected exactly for the desired application. In addition, it is possible that surprising results such as the formation of complex 20 (Figure 9), may occur., Die Ergebnisse der Arbeit sind auf vier unterschiedliche Themenbereiche aufgeteilt. Im ersten Themenbereich ging es um die Umsetzungen von CDPs mit Hexamethyldisilazanid-Komplexen. Hierbei wurden zum einen CDPPh und CDPcycl mit [Fe(HMDS)2] umgesetzt und die beiden Komplexe 1 und 2 (vgl. Abbildung 95) konnten erhalten und charakterisiert werden. Verbindung 1 wurde zuvor von KNEUSELS dargestellt und die Molekülstruktur mittels Einkristallröntgendiffraktometrie bestimmt.[103] 1 konnte in dieser Arbeit nun vollständig charakterisiert werden und es wurden weiterführende Untersuchungen mit Kooperationspartnern durchgeführt, um die magnetischen Eigenschaften und die Bindungsverhältnisse zwischen dem C0-Atom und dem Fe-Atom aufzuklären. Die theoretischen Berechnungen zeigen, dass es sich bei der Bindung zwischen C0 und dem Fe-Atom um eine Bindung mit hohem Doppelbindungsanteil handelt. Mit 2 konnte ein weiterer Komplex zwischen einem CDP und [Fe(HMDS)2] erhalten werden und dessen Molekülstruktur aufgeklärt werden. Weitere Untersuchungen magnetischer und theoretischer Art wurden an 2 bisher noch nicht durchgeführt. Somit fehlen Vergleiche zwischen 1 und 2. Des Weiteren gelang die erste literaturbekannte Darstellung von CDPs mit Alkalimetallkationen. Durch die Umsetzung mit einem Alkalimetall-HMDS, einem Metall(II)-HMDS-Salz und zwei Äq. CDP (CDPPh und CDPcycl) konnten die in Abbildung 96 erhaltenen Komplexe 3–6 erhalten werden. In den Komplexen wird das Gruppe-1-Kation von zwei CDP-Liganden komplexiert. Die genauere Betrachtung der Atomabstände sowie das Verhalten in Lösung legen die Vermutung nahe, dass es sich bei den Wechselwirkungen zwischen dem C0-Atom und den Alkalimetallkationen um eher schwache kovalente Wechselwirkungen handelt. Untermauert wird diese Vermutung durch mehrere Atomabstände innerhalb der VdW-Radien zwischen den Atomen der Phenylgruppen der CDP-Liganden und dem Alkalimetallkationen. Die hieraus resultierenden Dispersions-wechselwirkungen schwächen indirekt die Bindung zwischen C0 und dem Alkalimetallkation. Dieses wird bei einem Vergleich der CDPs deutlich. Das CDPPh weist einen größeren Alkalimetall–C0-Atomabstand auf als in den Komplexen mit dem CDPcycl. Dafür gibt es bei den Komplexen 3 und 5 mehr Kontakte innerhalb der Summe der VdW-Radien als bei 4 und 6. Um die Art der Wechselwirkungen zwischen den CDP und dem Alkalimetallkation genau bestimmen zu können, sollten in Zukunft weiterführende quantenchemische Rechnungen durchgeführt werden, damit die einzelnen Anteile der verschiedenen Wechselwirkungen quantifiziert werden können. Der zweite Themenbereich beschäftigte sich mit der Darstellung neuer Carbodiphosphorane ausgehend vom CDPCl. Hierbei sollten die neuen CDPs durch eine Methathesereaktion dargestellt werden. Hierzu wurde eine Vielzahl an Substraten getestet. Es gelang die Darstellung der literaturbekannten CDPs CDPNMe2 (8) und CDPNEt2, wobei letzteres nur in seiner protonierten Form (9) als Chloridsalz charakterisiert werden konnte (vgl. Abbildung 97). Hierdurch konnte zwar der Beweis erbracht werden, dass der verfolgte Reaktionsweg funktioniert, dennoch nicht erhofften, einfachen Zugang zu einer Vielzahl an neuen CDPs bietet. Aufgrund dieses Befunds ist es nicht empfehlenswert, diesen Darstellungsweg für neue CDPs weiter zu verfolgen. Es sollte sich auf andere Darstellungswege konzentriert werden, um neuartige CDPs zu synthetisieren. Der dritte Themenbereich beschäftigte sich, aufbauend auf den Arbeiten von KNEUSELS, mit der Umsetzung von CDPs mit Gruppe-15-Verbindungen. Hierbei synthetisierte KNEUSELS die in Abbildung 98 dargestellten Verbindungen 10, 12 und 13 und bestimmte ihre Molekülstruktur. Für diese Verbindungen konnte die Vervollständigung der Analytik durch umfangreiche NMR-Studien abgeschlossen werden. Zudem gelang es, das in Abbildung 99 dargestellten CDPPh-Arsen-Addukt 11 zu synthetisieren und vollständig zu charakterisieren und somit die Reihe der Gruppe 15 Verbindungen des CDPPh zu vervollständigen. Weiterführend wurden die Reaktivitäten von 10 und 13 untersucht. Hierbei konnte der in Abbildung 100 dargestellte Komplex 14, durch die Umsetzung von 13 mit TMS-OTf, erhalten werden. Dieser zeigt Anzeichen von unerwartetem Dissoziationsverhalten in Lösung: so lassen erste NMR-Studien vermuten, dass die Trifluormethan-sulfonatanionen in Lösung frei vorliegen. Weiter aufbauend auf den Befunden von KNEUSELS und der von ihm gefundenen intramolekularen elektrophilen aromatischen Substitution wurde der zu 10 analoge Komplex 16 mit CDPcycl (vgl. Abbildung 101) dargestellt. Mit 16 wurde, leider bisher vergeblich, versucht intermolekular Aromaten zu einer Substitutionsreaktion zu bringen. Außerdem wurden systematisch Chloridsubstituenten von 16 gegen Phenylgruppen ausgetauscht und die in Abbildung 101 gezeigten Verbindungen 17 und 18 erhalten. Die Komplexe 16–18 konnten mittels NMR-Analytik sowie DFT-Methoden untersucht werden. Hierdurch ließ sich der Einfluss auf die Bindung zwischen CDPcycl und dem P-Atom als Zentralatom zeigen. So nimmt mit die Kopplungskonstante der 2JPP-Kopplung mit sinkender Elektronendichte am zentralen Phosphoratom ab. In den DFT-Rechnungen lässt sich mit steigender Elektronendicht am zentralen P-Atom auch eine relative Zunahme des Orbitalkoeffizienten am C0 (HOMO) erkennen. Weiterführende Untersuchungen auf diesem Gebiet sollten sich auf die elektrophile aromatische Substitution stützen, um so neue Verbindungen zu erzeugen. Der vierte Teilbereich dieser Arbeit beschäftigte sich mit der elektrosterischen Charakterisierung von CDPs. Hierzu konnte CDPcycl durch die Synthese der in Abbildung 102 dargestellten Komplexe elektrosterisch charakterisiert und mit bekannten CDPs verglichen werden. Aus diesen zwei Komplexen konnte jeweils das %Vbur und aus Komplex 21 der TEP bestimmt werden. Das %Vbur von CDPcycl liegt mit 39.9–41.7% erwartungsgemäß leicht unter dem des CDPPh (41.9–43.4%). Mit einem TEP von 2024 cm−1 besitzt CDPcycl den niedrigsten TEP (höchste Gesamtdonorstärke) der bisher bekannten CDPs. Generell ist die elektrosterische Charakterisierung eine Methode, die angewendet werden sollte, um neue Liganden zu klassifizieren. Somit lassen sich die Liganden genau für den gewünschten Verwendungszweck auswählen. Zudem ist es möglich, dass es bei der Darstellung der benötigten Komplexe zu unerwartetem Reaktionsverhalten in Form der Bildung von Komplex 20 kommen kann, der in Abbildung 103 gezeigt ist.
- Published
- 2021
- Full Text
- View/download PDF
10. [Procedure Guideline for Prostate Cancer Imaging with PSMA-ligand PET/CT].
- Author
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Afshar-Oromieh A, Eiber M, Fendler W, Schmidt M, Rahbar K, Ahmadzadehfar H, Umutlu L, Hadaschik B, Hakenberg OW, Fornara P, Kurth J, Neels O, Wester HJ, Schwaiger M, Kopka K, Haberkorn U, Herrmann K, and Krause BJ
- Subjects
- Male, Humans, Positron Emission Tomography Computed Tomography methods, Ligands, Androgen Antagonists, Neoplasm Recurrence, Local, Gallium Radioisotopes, Prostate pathology, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology
- Abstract
PSMA-PET/CT for imaging prostate cancer (PC) has spread worldwide since its clinical introduction in 2011. The majority of experiences have been collected for PSMA-PET-imaging of recurrent PC. Data for primary staging of high-risk PC are highly promising. Meanwhile, a plethora of PSMA-ligands are available for clinical use (e. g.
68 Ga-PSMA-11,68 Ga-PSMA-I&T,68 Ga-PSMA-617,18 F-DCFBC,18 F-DCFPyL,18 F-PSMA-1007,18 F-rhPSMA-7 and18 F-JK-PSMA-7). However, an official approval is available only for68 Ga-PSMA-11 (approved by the US FDA in 2020) and18 F-DCFPyL (approved by the US FDA in 2021).Recommendations for acquisition times vary from 1-2 h p. i. It has been shown that for the majority of tumour lesions, the contrast in PSMA-PET/CT increases with time. Therefore, additional late imaging can help to clarify unclear findings. PSMA-PET/CT should be performed prior to commencing an androgen deprivation therapy (ADT) since (long term) ADT reduces the visibility of PC lesions. Following injection of PSMA-ligands, hydration and forced diuresis are recommended for PSMA-ligands with primarily excretion via the kidneys in order to increase the visibility of tumour lesions adjacent to the urinary bladder.PSMA-ligands are physiologically taken up in multiple normal organs. For some18 F-labelled PSMA-ligands, presence of unspecific focal bone uptake has been reported. When using these tracers, focal bone uptake without CT-correlate should be interpreted with great caution. Besides prostate cancer, practically all solid tumors express PSMA in their neovasculature thereby taking up PSMA-ligands, although usually at a lower extent compared to PC. Also multiple benign lesions and inflammatory processes (e. g. lymph nodes) take up PSMA-ligands, also usually at lower extent compared to PC., Competing Interests: Erklärung zu finanziellen InteressenForschungsförderung erhalten: Nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Sponsor der Veranstaltung): nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Nicht-Sponsor der Veranstaltung): ja.Erklärung zu nichtfinanziellen InteressenDie Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
11. [Role of innate receptors in chronic inflammation and autoimmunity].
- Author
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Babic M and Romagnani C
- Subjects
- Carrier Proteins, Cytokines metabolism, Humans, Inflammation, Ligands, Toll-Like Receptors, Autoimmunity, NK Cell Lectin-Like Receptor Subfamily K metabolism
- Abstract
Elucidating the basis of chronic disease courses and the development of appropriate treatment methods for inflammatory diseases still represent a big challenge for medical science, as the mechanisms driving aberrant immune reactions are mostly still unknown. Of particular interest is the identification of checkpoints that regulate the function and differentiation of proinflammatory cells during the pathogenesis, along with methods for modulation of specific checkpoints as a treatment approach. Innate receptors, such as members of the natural killer group 2 family (NKG2X), natural cytotoxicity receptors (NCR) or Toll-like receptors (TLRs), play an important role in modulating the immune response. NKG2 member D (NKG2D) is a potent activating receptor of the immune system, known as a sentinel for cellular danger signals presented by cells exposed to endoplasmic reticulum (ER) stress, cell death or an inflammatory cytokine milieu. NKG2A/C bind the non-classical HLA class I molecule, sense changes in ligand expression associated with malignant transformation and cellular stress and their main function is to send inhibitory or activating signals to NK cells and subsets of T cells. In this review, we present our latest knowledge on the understanding of the role of innate receptors in the context of chronic inflammation and autoimmunity with special emphasis on danger sensor receptors NKG2D and NKG2A/C., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
12. [Oncological theranostics in nuclear medicine].
- Author
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Laschinsky C, Herrmann K, Fendler W, Nader M, Lahner H, Hadaschik B, and Sandach P
- Subjects
- Humans, Iodine Radioisotopes therapeutic use, Ligands, Male, Positron Emission Tomography Computed Tomography methods, Positron-Emission Tomography, Precision Medicine, Radiopharmaceuticals therapeutic use, Theranostic Nanomedicine methods, Nuclear Medicine, Prostatic Neoplasms drug therapy
- Abstract
The theranostic principle describes the diagnostic and therapeutic use of radioactive nuclides linked to biochemically active ligands. The oldest and most prominent field of application of theranostics in oncology is differentiated thyroid cancer treated by radioiodine therapy, which allows imaging of the iodine uptake and thus tumor manifestations by gamma (γ) radiation of radioiodine. Other areas of application include neuroendocrine tumors, castration-resistant prostate cancer and, in the context of individual therapeutic approaches, fibroblastic tumors. Imaging with beta-plus (β
+ ) emitters is mainly performed using so-called hybrid imaging: positron emission tomography (PET) in combination with computed tomography or magnetic resonance imaging (PET/CT or PET/MRI). Beta-minus (β- ) emitters are predominantly used in therapy, but the use of alpha (α) emitters is also increasing, thus, enabling targeted cancer treatment with mostly low-grade side effects., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)- Published
- 2022
- Full Text
- View/download PDF
13. Teaching Enantioselectivity to C–H Bond Functionalizations: Initial Steps of a Rather Long Shot
- Author
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Nicolai Cramer
- Subjects
Asymmetric catalysis ,C–h activation ,Ligands ,Palladium ,Rhodium ,Chemistry ,QD1-999 - Abstract
The direct functionalization of non-activated C–H bonds, especially in an enantioselective manner, requires metal catalysts equipped with ligands with specifically designed properties. Examples for asymmetric C(sp2)–H and C(sp3)–H functionalizations using palladium- and rhodium catalysts are shown. This work was rewarded by the 2012 Werner Prize of the Swiss Chemical Society.
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- 2012
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14. [PSMA-based theranostics for prostate cancer : From imaging to treatment]
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H, Ilhan, C, la Fougère, and B J, Krause
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Diagnostic Imaging ,Glutamate Carboxypeptidase II ,Male ,Prostate ,Prostatic Neoplasms ,Ligands ,Sensitivity and Specificity ,Theranostic Nanomedicine ,Radioligand Assay ,Treatment Outcome ,Positron Emission Tomography Computed Tomography ,Antigens, Surface ,Humans ,Precision Medicine ,Radiopharmaceuticals - Abstract
In recent years nuclear medicine theranostics using radiolabeled prostate-specific membrane antigen (PSMA) ligands have gained increasing importance in the management of prostate cancer.The aim of this work is to highlight the value of theranostic concepts using radiolabeled PSMA ligands for both the diagnostic work-up and treatment of advanced prostate cancer.The currently available knowledge in the literature is summarized and presented.The use of PSMA in positron emission tomography-computed tomography (PET/CT) shows a high sensitivity and specificity for prostate cancer imaging, particularly in patients with biochemical recurrences. Furthermore, promising results are also reported for staging of primary prostate cancer and treatment monitoring. In addition, radioligand therapy using alpha and beta emitters is a promising third line treatment option in intensively pretreated patients with metastases. The reduction of side effects and optimization of the treatment sequence of radioligand therapy is of increasing importance.Nuclear medicine theranostics have an increasing clinical impact on the diagnostics and treatment of prostate cancer.
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- 2020
15. [PSMA radioligand therapy in patients with advanced prostate cancer]
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M, Bögemann, K, Herrmann, J P, Radtke, and K, Rahbar
- Subjects
Male ,Heterocyclic Compounds, 1-Ring ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,Germany ,Humans ,Prostatic Neoplasms ,Dipeptides ,Lutetium ,Prostate-Specific Antigen ,Radiopharmaceuticals ,Ligands - Abstract
Based on significant progress in recent years, metastatic castration-resistant prostate cancer (mCRPC) patients can be treated better and better. The medications include androgen signaling inhibitors, chemotherapy,Establishment of status quo ofPresentation of the therapy landscape in mCRPC and the current evidence onSeveral larger retrospective studies and the first prospective trials onDespite the promising preliminary results of
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- 2020
16. Die Expression der Todesrezeptorsysteme TRAIL-R1/-R2/-R4, CD95 und TNFR1 und ihrer Liganden im duktalen Adenokarzinom des Pankreas
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Gärtner, Friederike, Kalthoff, Holger, and Halske, Christine
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Immunohistochemistry, PDAC ,doctoral thesis ,Abschlussarbeit ,ligands ,Death receptors ,TNFR-SF ,TRAIL ,ddc:610 ,ddc:6XX ,TNF alpha ,CD 95 - Abstract
The expression of five members of the TNF receptor superfamily and two of their ligands in human pancreatic ductal adenocarcinoma was analysed by immunohistochemistry. 41 patients with histologically confirmed ductal carcinoma of the pancreas were enrolled in this study in order (i) to compare the individual TNFR-SF expression and their ligands in PDAC-cells and (ii) to investigate their correlation with survival data. All patients had undergone pancreaticoduodenectomy and were staged as pT3N1M0. Immunostaining was done on FFPE tissue sections of the tumor tissue, using antibodies directed against TRAIL-Receptor-1, -2 and -4, TRAIL, CD95, TNF-Receptor-1 and TNF-α. The intensity and quantity of immunostaining were evaluated separately for tumor cell cytoplasm and tumor cell nucleus. Immunostaining results were correlated with each other and with patient survival. All proteins were found to be expressed in the majority of the tumor cells. The expression (i) of the following members of TNFR-SF and their ligands correlated with each other: TNF-Receptor-1 and TNFα (cytoplasmatic scores, p= 0.001), TNF-Receptor 1 and TRAIL (nuclear antigen expression p= 0.005 and the main score p= 0.001, which contains the overall intracellular antigen expression), TNF-Receptor 1 and CD95 (main score, p= 0.001), TRAIL-Receptor-1 and TRAIL-Receptor-2 (nuclear parameters, p= 0.023), TRAIL-Receptor-4 and TRAIL (main score p= 0.041). In addition (ii), high cytoplasmatic expression of TNF-Receptor-1 and a strong cytoplasmatic and nuclear expression of CD95 correlated significantly with a better survival prognosis of PDAC patients.
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- 2020
17. Positronenemissionstomographie (PET) in der Schmerzforschung.
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Sprenger, T., Henriksen, G., Valet, M., Platzer, S., Berthele, A., and Tölle, T.R.
- Abstract
Copyright of Der Schmerz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2007
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18. [Radio- and photosensitization of plasmid DNA by DNA binding ligand propidium iodide: Investigation of Auger electron induction and detection of Cherenkov-emission]
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Jörg, Kotzerke, Roswitha, Runge, Pauline, Götze, Gerd, Wunderlich, Wolfgang, Enghardt, and Robert, Freudenberg
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Photosensitizing Agents ,Electrons ,DNA ,Ligands ,Radiation Tolerance ,Plasmids ,Propidium - Abstract
We investigated whether propidium iodide (PI) enhances DNA damaging effects of ionizing and non-ionizing radiation species (X-rays, alpha-, beta-, auger electron emission and light of various wavelengths, respectively). This biophysical experimental setting allowed us, furthermore, to investigate whether Cherenkov emission can be detected by photodynamic effects and increased DNA damage.Conformation changes of plasmid DNA were detected and quantified by gelelectrophoresis and fluorescence imaging. Hydrogen peroxide, stannous dichloride, and dimethylsulfoxide were used as chemical modulators, Tc-99m, Re-188, Ra-223, and x-ray (32 kV and 200 kV) reflected radiotoxicity and light (λ = 254 nm, 366 nm and 530-575 nm) induced phototoxicity.Radiotracers and x-rays induced dose dependent DNA damage. PI did not serve as radiosensitizer in radioisotopes, while a low effect was detected in X-rays. The phototoxicity was dependent on the wavelengths of light. Light with a wavelength range of 530-575 nm in combination with PI resulted in direct DNA damage. The yield of Cherenkov emission was far below the photon emission of light irradiation and not distinguishable from general radiotoxicity.PI binds to plasmid DNA, is not chemotoxic, and increases radiotoxicity only to minor extent. Phototoxicity and its stimulation by PI is dependent on the wavelength of the light. No kind of energy deposition was capable of inducing an Auger electron cascade. Furthermore, no increase in DNA damage induced by photodynamic effects from Cherenkov emission was detectable.ZIEL: Untersucht wurde, ob Propidiumiodid (PI) die DNA-schädigende Wirkung von ionisierender und nicht ionisierender Strahlung (Röntgenstrahlung, Alpha-, Beta-, Auger-Elektronen-Strahlung bzw. Licht diverser Wellenlängen) verstärken kann. Diese biophysikalische Versuchsanordnung ermöglicht es zu überprüfen, ob Cherenkov-Strahlung in relevantem Umfang via photodynamischer Effekte und erhöhter DNA-Schädigung nachweisbar ist.Konformationsänderungen der Plasmid-DNA durch DNA-Schäden wurden mittels Gelelektrophorese und Fluoreszenzfärbung detektiert und quantifiziert. Wasserstoffperoxid, Zinndichlorid und Dimethylsulfoxid wurden als chemische Modulatoren, Tc-99m, Re-188, Ra-223 und Röntgenstrahlung (32 kV und 200 kV) zur Bestimmung der Radiotoxizität und Licht (λ = 254 nm, 366 nm und 530–575 nm) zur Bestimmung der Phototoxizität eingesetzt.Die Radiotracer und die Röntgenstrahlung verursachten dosisabhängige DNA-Schäden. PI fungierte nicht als Radio-Sensitizer bei den Radionukliden und nur in geringem Maß bei Röntgenstrahlung. Die Phototoxizität war abhängig von der Wellenlänge. Licht im Wellenlängenbereich von 530–575 nm (VIS) resultierte in Kombination mit PI in direkten DNA-Schäden. Die Ausbeuten der Cherenkov-Strahlung lagen weit unter der Photonen-Emission der Lichtbestrahlung und konnten daher von der Radiotoxizität nicht unterschieden werden.PI bindet an Plasmid-DNA, ist nicht chemotoxisch und steigert kaum die Radiotoxizität. Die Phototoxizität und die Wirkung von PI sind abhängig von der Wellenlänge. Keine Art der Energiezufuhr konnte via PI eine Auger-Elektronen-Kaskade induzieren. Auch eine erhöhte DNA-Schädigung durch photodynamische Effekte via Cherenkov-Strahlung war nicht nachweisbar.
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- 2019
19. Inverse PPARβ/δ Agonisten: Rekrutierung von Co-Repressoren und Mechanismen der transkriptionellen Repression
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Legrand, Nathalie and Adhikary, Till (PD Dr.)
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reinitiation ,Co-Repressoren ,HDAC3 ,RNA-Polymerase II ,Kernrezeptoren ,Liganden ,Reinitiation ,Medizin, Gesundheit ,Mediator ,SMRT ,nuclear receptors ,ini ,inverse agonists ,ligands ,PPARβ/δ ,NCoR ,inverse Agonisten ,Transkription ,Ini ,co-repressors ,RNA polymerase II ,transcription ,Medical sciences, Medicine ,ddc:610 - Abstract
Der Peroxisomen-Proliferator-aktivierte Rezeptor β/δ (PPARβ/δ) bindet als Klasse II Kernrezeptor mit seinem obligatorischen Heterodimerisierungspartner RXR an PPAR-responsive Elemente (PPREs) der DNA. Im unligierten Zustand übt PPARβ/δ durch die Rekrutierung von NCoR/SMRT-Komplexen eine basale Repression auf die Transkription seiner kanonischen Zielgene aus. Die Bindung eines Agonisten führt zur Dissoziation dieser Co-Repressoren und ermöglicht die Rekrutierung von Co-Aktivatoren, was letztlich in einer Aktivierung der Transkription resultiert. Synthetische inverse Agonisten bewirken hingegen eine verstärkte Repression, die eine Aktivierung der Transkription des Zielgens ANGPTL4 durch verschiedene Stimuli auf dominante Weise unterdrückt. Die TGFβ-vermittelte Induktion der ANGPTL4-Transkription ist ein zentraler fördernder Schritt im Metastasierungsprozess von Brustkrebszellen. Aufgrund ihrer Eigenschaften, diese transkriptionelle Aktivierung von ANGPTL4 dominant zu unterbinden, sind inverse PPARβ/δ Agonisten vielsprechende Kandidaten in der Wirkstoffentwicklung zur Behandlung von Neoplasien. Der zugrundeliegende Mechanismus war weitgehend unverstanden, und Experimente unserer Arbeitsgruppe wiesen zunächst darauf hin, dass der dominant-repressive Effekt nicht durch NCoR/SMRT-Komplexe und die Deacetylase-Aktivität ihrer HDAC3-Untereinheit vermittelt wird. Die vorliegende Arbeit befasst sich mit der Aufklärung des Mechanismus der transkriptionellen Repression durch inverse PPARβ/δ Agonisten. Dabei diente das besonders stark durch PPARβ/δ Liganden regulierte Zielgen ANGPTL4 als Modell-Locus. In ChIP-qPCR Experimenten konnte gezeigt werden, dass der inverse PPARβ/δ Agonist PT-S264 den Ablauf der Transkription von PPARβ/δ Zielgenen am Schritt der Initiation bzw. Reinitiation beeinträchtigt. Es wurde eine verminderte Rekrutierung aktivierender Untereinheiten des Mediator-Komplexes (MED1, MED26 und MED13L) sowie des generellen Transkriptionsfaktors (GTF) TFIIB und der RNA-Polymerase II zum ANGPTL4 Promotor festgestellt. Die Rekrutierung anderer GTFs wie TFIIA wird hingegen nicht beeinflusst. Aus der Literatur ist bekannt, dass der Mediator-Komplex die Rekrutierung von TFIIB unterstützt und dass sowohl der Mediator-Komplex als auch TFIIB für die Rekrutierung der RNA-Polymerase II zum Präinitiationskomplex erforderlich sind. Somit könnte letztlich die beeinträchtige Rekrutierung von aktivierenden Mediator-Untereinheiten (oder des gesamten Mediator-Komplexes) für die Beeinträchtigung der Rekrutierung von TFIIB und der RNA-Polymerase II ursächlich sein. Zur Identifikation von Co-Repressoren, die in Anwesenheit eines inversen Agonisten von PPARβ/δ rekrutiert werden, wurden ChIP-massenspektrometrische Analysen durchgeführt. Komponenten der NCoR/SMRT-Komplexe wurden als spezifische Interaktoren bei Bindung des inversen Agonisten PT-S264 detektiert. Unter den PT-S264 abhängigen Interaktoren fanden sich darüber hinaus keine anderen bekannten Co-Repressoren. Die verstärkte Rekrutierung von NCoR/SMRT-Komplexkomponenten durch PPARβ/δ bei Bindung des inversen Agonisten konnte in ChIP-qPCR Experimenten bestätigt werden. Um weitere Erkenntnisse über die transkriptionelle Regulation durch PPARβ/δ und insbesondere die Bindung der in Anwesenheit von PT-S264 rekrutierten Co-Repressoren zu gewinnen, wurde ein funktioneller Screen von 80 PPARβ/δ-Mutanten durchgeführt. MDA-MB-231-luc2 PPARD KO Zellen wurden retroviral mit mutierten PPARD cDNAs transduziert und auf eine Beeinträchtigung der transkriptionellen Regulation des Zielgens ANGPTL4 untersucht. Dabei wurden, neben der verstärkten Repression durch den inversen PPARβ/δ Agonisten PT-S264, auch die basale Repression und die Aktivierung durch den PPARβ/δ Agonisten L165,041 betrachtet. Mehrere in diesem funktionellen Screen identifizierte Mutanten zeigten einen Verlust der basalen Repression und waren von besonderem Wert für die weitere Untersuchung des Mechanismus der Repression durch inverse PPARβ/δ Agonisten. So zeigte sich im Basalzustand gegenüber den mit Wildtyp PPARβ/δ rekonstituierten Zellen eine verminderte Anwesenheit von NCoR/SMRT-Komplexkomponenten an PPREs von PPARβ/δ Zielgenen, die mit einer vermehrten Rekrutierung der RNA-Polymerase II an die Promotoren einherging. Durch den inversen Agonisten PT-S264 konnte die Rekrutierung von NCoR/SMRT-Komplexkomponenten und die daraus resultierende verminderte Rekrutierung der RNA-Polymerase II zum Promotor in den Mutanten wiederhergestellt werden. Diese Ergebnisse legen nahe, dass sowohl die basale Repression als auch die Repression durch inverse PPARβ/δ Agonisten von NCoR/SMRT-Komplexen vermittelt werden. Die Rolle der enzymatischen Untereinheit der NCoR/SMRT-Komplexe HDAC3 bei der Repression wurde durch den Einsatz von Deacetylase-Inhibitoren überprüft. Dabei verhielten sich die basale Repression und die Repression durch den inversen Agonisten größtenteils insensitiv gegenüber der Inhibition von Deacteylase-Aktivität. Somit deuten die Ergebnisse der vorliegenden Arbeit darauf hin, dass NCoR/SMRT-Komplexe die transkriptionelle Repression durch inverse PPARβ/δ Agonisten über Deacetylase-abhängige und Deacetylase-unabhängige Mechanismen vermitteln. Die Unterdrückung der Rekrutierung von aktivierenden Mediator-Untereinheiten ist wahrscheinlich ursächlich für das Ausbleiben der Rekrutierung von TFIIB und der RNA-Polymerase II zum Transkriptionsstart. Somit wird letztlich die Transkription am Schritt der Initiation bzw. Reinitiation gestört. Abschließend wurden zwei Hypothesen aufgestellt, die interessante Fragestellungen für zukünftige Projekte aufwerfen: I. NCoR bzw. SMRT verhindern die Bildung eines aktiven Initiationskomplexes durch die direkte Inhibition von Acetyltransferase-Aktivität oder durch andere deacetylase-unabhängige Mechanismen. II. NCoR bzw. SMRT verhindern Kontakte zwischen regulatorischen Elementen und dem Promotor durch die Regulation von Chromatin-Interaktionen. Angesichts der Stabilisierung von Cohesin-Komplexen durch Acetylierungen könnte dies in direktem Zusammenhang mit Hypothese I stehen., The class II nuclear receptor peroxisome proliferator activated receptor β/δ (PPARβ/δ) binds with its obligate heterodimerization partner RXR to PPAR responsive elements (PPREs) of the DNA. In the unliganded state, PPARβ/δ exerts basal repression on the transcription of its canonical target genes by recruiting NCoR/SMRT complexes. Binding of an agonist leads to the dissociation of these co-repressors and allows for co-activator recruitment, which results in activation of transcription. On the other hand, synthetic inverse agonists provoke reinforced repression, which prevents transcriptional induction of the target gene ANGPTL4 by different stimuli in a dominant manner. TGFβ mediated induction of ANGPTL4 transcription is a central promoting step in metastasis of breast cancer cells. Based on their ability to suppress this transcriptional activation of ANGPTL4, PPARβ/δ inverse agonists are promising candidates for the development of antineoplastic agents. The underlying mechanism of repression was largely unknown, and experiments of our group initially indicated, that the dominant repressive effect is not mediated by NCoR/SMRT complexes and the deacetylase activity of its HDAC3 subunit. The present thesis addresses the elucidation of the mechanism of transcriptional repression by PPARβ/δ inverse agonists. ANGPTL4 regulation by PPARβ/δ ligands is particularly strong, and this gene was therefore used as model locus. ChIP-qPCR experiments showed that the PPARβ/δ inverse agonist PT-S264 impairs transcription at the initiation or reinitiation step, respectively. Diminished recruitment of activating subunits of the Mediator complex (MED1, MED26 and MED13L) as well as the general transcription factor (GTF) TFIIB and RNA polymerase II to the ANGPTL4 promotor was detected. In contrast, recruitment of other GTFs such as TFIIA was not affected. It is known from literature, that the Mediator complex supports recruitment of TFIIB and that both, Mediator and TFIIB, are necessary for the recruitment of RNA polymerase II to the preinitiation complex. Therefore, the impaired recruitment of activating Mediator subunits (or the entire Mediator complex) could be causative for the impairment of TFIIB and RNA polymerase II recruitment. To identify co-repressors, which are recruited to PPARβ/δ in the presence of inverse agonists, ChIP mass spectrometry analyses were perfomed. Components of NCoR/SMRT complexes were detected as specific interactors upon binding of PT-S264. Among the PT-S264 dependent interactors no other known co-repressors were identified. The increased recruitment of NCoR/ SMRT complex components by PPARβ/δ upon binding of the inverse agonist was validated in ChIP-qPCR experiments. To obtain further insights into transcriptional regulation by PPARβ/δ and particularly the binding of co-repressors recruited in the presence of PT-S264, a functional screen of 80 PPARβ/δ mutants was performed. MDA-MB-231-luc2 PPARD KO cells were retrovirally transduced with mutant PPARD cDNAs and tested for an impairment of transcriptional regulation of the target gene ANGPTL4. Besides reinforced repression by the PPARβ/δ inverse agonist PT-S264, basal repression in the absence of synthetic ligands and activation by the PPARβ/δ agonist L165,041 were analysed. Several mutants identified in the functional screen showed a loss of basal repression and were of value for further investigation of the mechanisms. Compared to cells transduced with wildtype PPARβ/δ, reduced presence of NCoR/SMRT complex components at the PPREs of PPARβ/δ target genes was detected in the basal state, which was accompanied by increased recruitment of RNA polymerase II at their promoters. In cells expressing the mutants, recruitment of NCoR/SMRT complex components and the resulting diminished recruitment of RNA polymerase II to the promoter was restored by the PPARβ/δ inverse agonist PT-S264. These findings suggest that both basal repression by unliganded PPARβ/δ and repression by the PPARβ/δ inverse agonist are mediated by NCoR/SMRT complexes. The role of the HDAC3 subunit of NCoR/SMRT complexes in repression was tested by the use of deacetylase inhibitors. Basal repression as well as repression by the inverse agonist were largely insensitive to inhibition of deacetylase activity. Taken together, the results of the present thesis indicate that NCoR/SMRT complexes mediate the transcriptional repression by PPARβ/δ inverse agonists by both deacetylase-dependent and deacetylase-independent mechanisms. Prevention of recruitment of activating Mediator sub-units is probably causative for diminished TFIIB and RNA polymerase II recruitment to the transcription start site. Consequently, transcription is impaired at the initiation or reinitiation step. In conclusion, two hypotheses were proposed, which raise interesting questions for future approaches: I. NCoR and/ or SMRT prevent the formation of an active initiation complex by direct inhibition of acetyltransferase activity or through other mechanisms which do not rely on deacetylase activity. II. NCoR and/ or SMRT prevent contacts between regulatory elements and the promotor by regulating chromatin interactions. Given the stabilization of cohesin complexes by acetylation, this could be directly linked to hypothesis I.
- Published
- 2019
20. [Lutetium-177-PSMA radioligand therapy : Consensus within the framework of GKV-funded care between the university hospitals in Aachen, Bonn, Düsseldorf, Essen, and Cologne and the MDK Nordrhein]
- Author
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H, Ahmadzadehfar, P, Albers, A, Bockisch, M, Boegemann, C, Böhme, W, Burchert, M, Dietlein, A, Drzezga, U, Fabry, G, Feldmann, A, Heidenreich, A, Heinzel, K, Herrmann, A, Heyll, C, Höhling, C, Kreuzer, D, Laufer, R, Mengel, F M, Mottaghy, H-W, Müller, S C, Müller, E, Ost, K, Rahbar, W, Reifenhäuser, M, Schäfers, C, Schlenkhoff, M, Schmidt, I, Schmidt-Wolf, C, Wildenhain, B, Zimmer, and M, Essler
- Subjects
Male ,Radioisotopes ,Consensus ,Insurance, Health ,Health Care Costs ,Lutetium ,Ligands ,Hospitals, University ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,Germany ,Antigens, Surface ,Insurance, Health, Reimbursement ,Humans - Abstract
In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.
- Published
- 2018
21. [Kit-based radiolabeling of PSMA ligands]
- Author
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T, Derlin
- Subjects
Humans ,Prostatic Neoplasms ,Radiopharmaceuticals ,urologic and male genital diseases ,Ligands ,Article - Abstract
(68)Ga-labeled urea-based inhibitors of the prostate-specific membrane antigen (PSMA), such as (68)Ga-labeled N,N’-bis(2-hydroxybenzyl)-ethylenediamine-N,N’-diacetic acid (HBED)-PSMA-11, are promising small molecules for targeting prostate cancer. A new radiopharmaceutical, (68)Ga-labeled tris(hydroxypyridinone) (THP)-PSMA, has a simplified design for single-step kit-based radiolabeling. It features the THP ligand, which forms complexes with (68)Ga(3+) rapidly at a low concentration, at room temperature, and over a wide pH range, enabling direct elution from a (68)Ge/(68)Ga generator into a lyophilized radiopharmaceutical kit in 1 step without manipulation. The aim of this phase 1 study was to assess the safety and biodistribution of (68)Ga-THP-PSMA. METHODS: Cohort A comprised 8 patients who had proven prostate cancer and were scheduled to undergo prostatectomy; they had Gleason scores of 7–10 and a mean prostate-specific antigen level of 7.8 μg/L (range, 5.4–10.6 μg/L). They underwent PET/CT after the administration of (68)Ga-THP-PSMA. All patients proceeded to prostatectomy (7 with pelvic nodal dissection). Dosimetry from multi-time-point PET imaging was performed with OLINDA/EXM. Cohort B comprised 6 patients who had positive (68)Ga-HBED-PSMA-11 PET/CT scanning results and underwent comparative (68)Ga-THP-PSMA scanning. All patients were monitored for adverse events. RESULTS: No adverse events occurred. In cohort A, 6 of 8 patients had focal uptake in the prostate (at 2 h: average SUV(max), 5.1; range, 2.4–9.2) and correlative 31 staining of prostatectomy specimens on PSMA immunohistochemistry. The 2 (68)Ga-THP-PSMA scans with negative results had only 1+1/2+ staining. The mean effective dose was 2.07E-02 mSv/MBq. In cohort B, (68)Ga-THP-PSMA had lower physiologic background uptake than (68)Ga-HBED-PSMA-11 (in the parotid glands, the mean SUVmax for (68)Ga-THP-PSMA was 3.6 [compared with 19.2 for (68)Ga-HBED-PSMA-11]; the respective corresponding values in the liver were 2.7 and 6.3, and those in the spleen were 2.7 and 10.5; P < 0.001 for all). In 5 of 6 patients, there was concordance in the number of metastases identified with (68)Ga-HBED-PSMA-11 and (68)Ga-THP-PSMA. Thirteen of 15 nodal abnormalities were subcentimeter. In 22 malignant lesions, the tumor-to-liver contrast with (68)Ga-THP-PSMA was similar to that with (68)Ga-HBED-PSMA (4.7 and 5.4, respectively; P = 0.15), despite a higher SUV(max) for (68)Ga-HBED-PSMA than for (68)Ga-THP-PSMA (30.3 and 10.7, respectively; P < 0.01). CONCLUSION: (68)Ga-THP-PSMA is safe and has a favorable biodistribution for clinical imaging. Observed focal uptake in the prostate was localized to PSMA-expressing malignant tissue on histopathology. Metastatic PSMA-avid foci were also visualized with (68)Ga-THP-PSMA PET. Single-step production from a Good Manufacturing Practice cold kit may enable rapid adoption.
- Published
- 2018
22. Advances in Homogeneous Catalysis Using Secondary Phosphine Oxides (SPOs): Pre-ligands for Metal Complexes
- Author
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Thierry Achard
- Subjects
Models, Molecular ,Phosphines ,Inorganic chemistry ,Homogeneous catalysis ,Phosphinous acids (pa) ,Ligands ,010402 general chemistry ,01 natural sciences ,Catalysis ,Metal ,chemistry.chemical_compound ,Transition metal ,QD1-999 ,010405 organic chemistry ,Chemistry ,Secondary phosphine oxides (spo) ,Oxides ,General Medicine ,General Chemistry ,Metal-catalysed reactions ,Tautomer ,Phosphinito complexes ,0104 chemical sciences ,Metals ,visual_art ,visual_art.visual_art_medium ,Phosphine - Abstract
The secondary phosphine oxides are known to exist in equilibrium between the pentavalent phosphine oxides (SPO) and the trivalent phosphinous acids (PA). This equilibrium can be displaced in favour of the trivalent tautomeric form upon coordination to late transition metals. This tutorial review provides the state of the art of the use of secondary phosphine oxides as pre-ligands in transition metal-catalysed reactions. Using a combination of SPOs and several metals such as Pd, Pt, Ru, Rh and Au, a series of effective and original transformations have been obtained and will be discussed here.
- Published
- 2016
23. Prediction of logP for Pt(II) and Pt(IV) complexes: Comparison of statistical and quantum-chemistry based approaches
- Author
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Igor V. Tetko, Hristo P. Varbanov, James Alexis Platts, Mona Talmaciu, Markus Galanski, Elisabetta Gabano, and Mauro Ravera
- Subjects
Octanol ,Quantum chemistry calculations ,010402 general chemistry ,Ligands ,01 natural sciences ,Biochemistry ,Quantum chemistry ,logP prediction ,Inorganic Chemistry ,chemistry.chemical_compound ,Computational chemistry ,Linear regression ,Lipophilicity ,Consensus model ,Model development ,Platinum ,Shake flask ,010405 organic chemistry ,Pt(II)/Pt(IV) complexes ,Linear Regression ,Neural Networks ,Pt(ii)/pt(iv) Complexes ,Quantum Chemistry Calculations ,Logp Prediction ,0104 chemical sciences ,Partition coefficient ,chemistry ,Models, Chemical ,Quantum Theory ,Neural networks - Abstract
The octanol/water partition coefficient, logP, is one of the most important physico-chemical parameters for the development of new metal-based anticancer drugs with improved pharmacokinetic properties. This study addresses an issue with the absence of publicly available models to predict logP of Pt(IV) complexes. Following data collection and subsequent development of models based on 187 complexes from literature, we validate new and previously published models on a new set of 11 Pt(II) and 35 Pt(IV) complexes, which were kept blind during the model development step. The error of the consensus model, 0.65 for Pt(IV) and 0.37 for Pt(II) complexes, indicates its good accuracy of predictions. The lower accuracy for Pt(IV) complexes was attributed to experimental difficulties with logP measurements for some poorly-soluble compounds. This model was developed using general-purpose descriptors such as extended functional groups, molecular fragments and E-state indices. Surprisingly, models based on quantum-chemistry calculations provided lower prediction accuracy. We also found that all the developed models strongly overestimate logP values for the three complexes measured in the presence of DMSO. Considering that DMSO is frequently used as a solvent to store chemicals, its effect should not be overlooked when logP measurements by means of the shake flask method are performed. The final models are freely available at http://ochem.eu/article/76903. (C) 2015 Elsevier Inc. All rights reserved.
- Published
- 2016
24. [PSMA radioligand therapy in patients with advanced prostate cancer].
- Author
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Bögemann M, Herrmann K, Radtke JP, and Rahbar K
- Subjects
- Dipeptides administration & dosage, Germany epidemiology, Heterocyclic Compounds, 1-Ring administration & dosage, Humans, Ligands, Lutetium, Male, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant pathology, Radiopharmaceuticals administration & dosage, Treatment Outcome, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms, Castration-Resistant radiotherapy, Radiopharmaceuticals therapeutic use
- Abstract
Background: Based on significant progress in recent years, metastatic castration-resistant prostate cancer (mCRPC) patients can be treated better and better. The medications include androgen signaling inhibitors, chemotherapy,
223 Ra, and sipuleucel-T. Most patients treated with these agents will still develop primary or secondary resistance against any given drug. The177 Lutetium-PSMA radioligand therapy (177 Lu-PSMA-RLT) represents a good reserve option and can be used within compassionate use provisions demonstrating promising efficacy in the majority of patients in Germany., Objectives: Establishment of status quo of177 Lu-PSMA-RLT in mCRPC in 2020., Materials and Methods: Presentation of the therapy landscape in mCRPC and the current evidence on177 Lu-PSMA-RLT after PubMed based literature search., Results: Several larger retrospective studies and the first prospective trials on177 Lu-PSMA-RLT show premature but encouraging evidence on177 Lu-PSMA-RLT to be a promising new option in mCRPC patients. The toxicity profile seems to be favorable. The phase III trial VISION aims to provide evidence for the approval of177 Lu-PSMA-RLT in combination with abiraterone or enzalutamide in patients having been pretreated with enzalutamide or abiraterone and docetaxel., Conclusions: Despite the promising preliminary results of177 Lu-PSMA-RLT, the efficacy results of VISION need to be awaited prior to using the therapy outside of compassionate use provisions.- Published
- 2020
- Full Text
- View/download PDF
25. [PSMA-based theranostics for prostate cancer : From imaging to treatment].
- Author
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Ilhan H, la Fougère C, and Krause BJ
- Subjects
- Diagnostic Imaging, Humans, Ligands, Male, Precision Medicine, Prostate diagnostic imaging, Prostate pathology, Prostatic Neoplasms therapy, Radioligand Assay, Radiopharmaceuticals therapeutic use, Sensitivity and Specificity, Treatment Outcome, Antigens, Surface metabolism, Glutamate Carboxypeptidase II metabolism, Positron Emission Tomography Computed Tomography, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms metabolism, Theranostic Nanomedicine methods
- Abstract
Background: In recent years nuclear medicine theranostics using radiolabeled prostate-specific membrane antigen (PSMA) ligands have gained increasing importance in the management of prostate cancer., Aim: The aim of this work is to highlight the value of theranostic concepts using radiolabeled PSMA ligands for both the diagnostic work-up and treatment of advanced prostate cancer., Material and Methods: The currently available knowledge in the literature is summarized and presented., Results: The use of PSMA in positron emission tomography-computed tomography (PET/CT) shows a high sensitivity and specificity for prostate cancer imaging, particularly in patients with biochemical recurrences. Furthermore, promising results are also reported for staging of primary prostate cancer and treatment monitoring. In addition, radioligand therapy using alpha and beta emitters is a promising third line treatment option in intensively pretreated patients with metastases. The reduction of side effects and optimization of the treatment sequence of radioligand therapy is of increasing importance., Conclusion: Nuclear medicine theranostics have an increasing clinical impact on the diagnostics and treatment of prostate cancer.
- Published
- 2020
- Full Text
- View/download PDF
26. Untersuchungen zur Anbindung von organischen Liganden an Sn/S-Cluster zum potenziellen Einfang von Übergangsmetallionen
- Author
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Leusmann, Eliza and Dehnen, Stefanie (Prof. Dr.)
- Subjects
complexes ,Zinn-Schwefel-Cluster ,Zinn ,ligands ,Chelatliganden ,Ligand ,Chemistry and allied sciences ,Schwefel ,Übergangsmetall ,Komplexchemie ,Organometallchemie ,tin ,sulfur ,transition metal ions ,Chemie -- Zinn -- Schwefel -- Ligand -- Übergangsmetall -- Zinn-Schwefel-Cluster -- Chelatliganden -- Komplexchemie -- Organometallchemie -- tin -- sulfur -- ligands -- complexes -- transition metal ions ,ddc:540 - Abstract
Three methods were developed to either functionalize the Sn/S cluster A, [(RSn)4S6] A with R: (Me)OCCH2CMe2, with organic substituents which can serve as complexating agents for transition metals or to functionalize A with precoordinated complexes. The first method consists of reacting a precoordinated transition metal complex possessing a hydrazone or hydrazine functionality with the keto groups of A. This approach was successfully demonstrated for ruthenocene, which was first activated as acetylruthenocene RcAcNNH2. The hydrazone compound readily reacted with A. Single crystal X-ray diffraction showed a reorganization of the inorganic cluster core from the Sn4S6 topology to Sn6S10, the topology, with preservation of four organic substituents in compound [(RRcSn)4Sn2S10] (RRc: CMe2CH2C(Me)=N–N=C(Me)Rc, Rc: (C5H5)2Ru) (2). This phenomenon was observed for all subsequently performed functionalizations of A as well. The electrochemical and optical properties of 2 were examined in detail. 2 shows broad luminescence band at 500 nm could be observed and attributed to both the inorganic cluster core and the metal organic ligand. Attempts to tether other, more reactive precoordinated transition metal complexes to A in the same fashion were unsuccessful. It appears that only stable, 18 valence electron complexes can be used to perform this functionalization without decomposition. The second method is to functionalize A with hydrazine first and subsequently react the hydrazone derivative A’ with aldehydes, ketones or acetales. During the course of the investigations, it became apparent that ketones show insufficient reactivity and that the more reactive aldehydes can be used for functionalization. Reaction of A with 3-Methyl-2-butenale led to the butene functionalized cluster [(RBuSn)4Sn2S10] with RBu: CMe2CH2C(Me)=N-N=C(H)C=CMe2. Tethering an acetale to the cluster was only successful in one case, using 2-Furaldehyde-diethyl acetale to produce the cluster [(RFuSn)4Sn2S10] with RFu: CMe2CH2C(Me)=N-N=C(H)C4H3O. This underlines the great influence of the acetale substituent on the reactivity of the whole molecule. Altogether, the hydrazone-functionalized cluster A’ is considerably less reactive than its ketone precursor A, so this method is generally the least promising route for functionalization. The third method combines A and hydrazone functionalized ligands possessing donor atoms to give products that can then react with transition metals. During the course of the investigations, it became evident that the reactivity of the hydrazines H2N-NHR towards A varies greatly depending on the organic substituents R. While 2-Hydrazinobenzothiazole reacts with A to form the functionalized cluster [(RBT Sn)4Sn2S10] with RBT : CMe2CH2C(Me)=N-N-[C(S,N)C2]C4H4, 2,2’:6’2”-4’-Hydrazino-Terpyridine doesn’t show any reaction, possibly due to its outstanding complexation properties which may come along with chelated tin atoms. Photoluminescene measurements on the furan and benzothiazole decorated clusters 5 and 6 in comparison with the ruthenocene decorated cluster in 2 show that the (metal)organic substituents influence the luminescence properties of the compounds as they show broader signals which in case of 5 are slided to smaller wavelengths. A series of aromatic substituents with ascending size from benzaldehyde to anthracene and hetero aromatic substituents with hetero atoms in different positions, e.g. (iso-)quinoline were tethered to A. The most promising compound for capturing transition metals in this series is the 2,2’-bipyridine decorated cluster [(R6−BipySn)4Sn2S10] with R6−Bipy: CMe2CH2C(Me)=N-N=C(Me)(C5H4N−C5H3N)) (23). Unfortunately, its reaction with transition metals has so far only produced metal complexes without a cluster core attached. It is not yet clear whether these complexes result from an excess of ligand during the reaction or whether the Lewis acidic transition metal salts in combination with water molecules formed from the condensation reaction lead to a break of the ketazine bond. The reaction of 23 with Bis(1,5-cyclooctadiene)diiridium(I)dichloride led to the completely unexpected complex {[(COD)3Ir3S2]SSnCl}2 (26·2 CH2Cl2. Quantum chemical investigations of the complex show a great amount of delocalization of the Ir3S2 fragments to the point of cluster orbitals, while the central Sn2S2 ring and its bonds to the Ir3S2 fragments are built through localized 2e2c-bonds. The last method appeared the most promising route of all three, although reactions with transition metal complexes didn’t lead to the desired product., Zur Funktionalisierung des Keton-funktionalisierten Sn/S-Clusters mit DD-Struktur in Verbindung A, [(RSn)4S6] mit R: (Me)OCCH2CMe2, mit organischen Substituenten,die der Komplexierung von Übergangsmetall-Ionen dienen, oder mit präkoordinierten Komplexen wurden drei Herangehensweisen entwickelt. Die erste Syntheseroute sieht vor, einen präkoordinierten Komplex mit Hydrazon oder Hydrazinfunktionalität über die Ketoeinheiten an A zu binden. Dieser Ansatz wurde erfolgreich für Ruthenocen durchgeführt. Die Molekülstruktur von Acetylruthenocen wurde erstmals durch Einkristallstrukturanalyse näher bestimmt. Mittels Einkristallstrukturanalyse genauer charakterisiert, änderte sich - wie auf Grund bereits publizierter Ergebnisse zu erwarten war - bei dieser Reaktion das anorganische Grundgerüst von Sn4S6 zu Sn6S10. Es blieben jedoch blieben vier organische Substituenten am ruthenocendekorierten Sn/S-Cluster mit BSC-Struktur erhalten. Der Ruthenocen-funktionalisierte Cluster [(RRcSn)4Sn2S10] (RRc: CMe2CH2C(Me)=N–N=C(Me)Rc, Rc: (C5H5)2Ru). Der Cluster zeigt gewisse Lumineszenzeigenschaften, und seine Emission in der Photolumineszenzuntersuchung weist ein breites Maximum auf bei einer Wellenlänge um 500 nm. Abgesehen von stabilen 18-VE-Komplexen gelang es nicht, präkoordinierte Komplexe an den Sn/S-Cluster anzubinden. Eine zweite Syntheseroute besteht darin, A zunächst als Hydrazon zu funktionalisieren (A’) und dann mit Aldehyden, Ketonen oder Acetalen umzusetzen. Diese Herangehensweise ist für Ketone nicht praktikabel, sehr wohl jedoch für Aldehyde. So konnte ein Buten-funktionalisierter Sn/S-Cluster erhalten werden. Die Anbindung eines Acetals an A’ war nur für 2-Furaldehyd-diethylacetal erfolgreich und führte zur Bildung von [(RFuSn)4Sn2S10]. In der Packung im Kristall zeigen die Furyl-Reste des Sn/S-Clusters mit BSC-Topologie π- Stacking-artige Interaktionen miteinander.* Insgesamt ist der Hydrazon-funktionalisierte Sn/S-Cluster A’ deutlich unreaktiver als sein Keton-Edukt. Die letzte Syntheseroute macht sich wiederum die Reaktivität von A zu Nutze, indem Hydrazon-funktionalisierte Liganden mit Donor-Atomen (oder substituierte Hydrazine) angebunden und die so erhaltenen Verbindungen anschließend mit Übergangsmetall-Ionen umgesetzt werden. Es zeigte sich, dass je nach organischem Substituenten nicht alle Hydrazine H2N-NHR bereitwillig mit A reagieren: So geht 2-Hydrazinobenzothiazol* eine Reaktion mit A ein und bildet [(RBT Sn)4Sn2S10] mit RBT : CMe2CH2C(Me)=N-N-[C(S,N)C2]C4H4, während 2,2’:6’,2”- 4’-Hydrazino-Terpyridin nicht umgesetzt wird – vermutlich aufgrund seiner hervorragenden komplexierenden Eigenschaften und damit einhergehender Chelatisierung der Sn-Atome. *Photolumineszenzuntersuchungen an furyl- und benzothiazoldekoriertem Cluster im Vergleich mit dem ruthenocendekorierten Cluster zeigen, dass die (metall- )organischen Substituenten die Leuchteigenschaften der Verbindungen beeinflussen, indem sie die Maxima zu anderen Wellenlängen hin verschieben. Eine Reihe von Aromaten in aufsteigender Größe (von Benzaldehyd bis Anthrazen) sowie mit Hetero-Atomen an verschiedenen Positionen (wie Chinolin und Isochinolin) konnte mit A zur Reaktion gebracht werden. Fast alle weisen eine Art π-Stacking zwischen den Aromaten auf und variieren von parallelem bis T-förmigem π-stacking. Das vielversprechendste Molekül für den weiteren Einfang von Übergangsmetallen stellt ein Bipyridin-dekorierter Sn/S-Cluster dar, [(R6−BipySn)4Sn2S10] mit R6−Bipy: CMe2CH2C(Me)=N-N=C(Me)(C5H4N−C5H3N)) (23). Die Umsetzungen mit Übergangsmetallkomplexen zeigten jedoch, dass ausschließlich Metall-Ion- Bipyridinderivat-Komplexe erhalten wurden, in denen sich das ringnahe N-Atom der Hydrazongruppe wie ein Terpyridin-N-Atom verhält ({Co[η3-(N,N-Bipy)]Cl2} und [Ru(dmso)η3-(N,N-Bipy)Cl2]). Ungeklärt bleibt, ob diese Komplexe aus einem Überschuss des Liganden resultieren oder ob die Lewis-sauren Übergangsmetalle in Verbindung mit den Wassermolekülen aus den Kondensationsreaktionen für einen Ketazin-Bindungsbruch sorgen, wie es auch für Protonen bekannt ist. Die Umsetzung von 23 mit Bis(1,5-cyclooctadien)diiridium(I)-dichlorid lieferte einen völlig neuartigen Komplex: {[(COD)3Ir3S2]SSnCl}2. Quantenchemische Untersuchungen dieser Verbindung zeigen, dass die Ir3S2-Fragmente einschließlich ihrer COD-Liganden eine starke Delokalisation bis hin zu Clusterorbitalen aufweisen, während der zentrale Sn2S2-Ring und seine Bindungen zu den Ir3S2-Fragmenten eher durch lokalisierte 2e−-2z-Bindungen gebildet werden.
- Published
- 2015
27. Synthesis and Characterization of Photoaffinity Probes that Target the 5-HT3 Receptor
- Author
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Thomas Jack, Martin Lochner, Oliver Mühlemann, Marc-David Ruepp, and Andrew J. Thompson
- Subjects
Models, Molecular ,Ultraviolet Rays ,Photo-labeling ,Photoaffinity Labels ,Ligands ,01 natural sciences ,5-HT3 receptor ,Granisetron ,03 medical and health sciences ,0302 clinical medicine ,Cell surface receptor ,Photoaffinity probes ,540 Chemistry ,Humans ,Binding site ,Receptor ,Serotonin receptor ,QD1-999 ,Ion channel ,Binding Sites ,biology ,010405 organic chemistry ,Chemistry ,General Medicine ,General Chemistry ,Small molecule ,Combinatorial chemistry ,0104 chemical sciences ,3. Good health ,Kinetics ,Diazomethane ,Structural biology ,Structural Homology, Protein ,Biophysics ,biology.protein ,570 Life sciences ,5-ht3 receptor ,Serotonin Antagonists ,Receptors, Serotonin, 5-HT3 ,030217 neurology & neurosurgery ,Protein Binding - Abstract
The 5-HT3 receptor is one of several ion channels responsible for the transmission of nerve impulses in the peripheral and central nervous systems. Until now, it has been difficult to characterize transmembrane receptors with classical structural biology approaches like X-ray crystallography. The use of photoaffinity probes is an alternative approach to identify regions in the protein where small molecules bind. To this end, we present two photoaffinity probes based on granisetron, a well known antagonist of the 5-HT3 receptor. These new probes show nanomolar binding affinity for the orthosteric binding site. In addition, we investigated their reactivity using irradiation experiments.
- Published
- 2014
28. Neuer Therapieansatz zur Behandlung des Sommerekzems beim Pferd auf molekularbiologischer und immunologischer Ebene: TACI-Ig als Kontrolle seiner pro-inflammatorischen Bindungspartner BAFF und APRIL
- Author
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Kühnel, Silvia
- Subjects
sweet itch ,treatment ,ligands ,Culicoides ,ELISA ,Horses ,eczema ,allergic reactions ,cytokines ,plasma cells ,B lymphocytes - Abstract
Bei dem Sommerekzem der Pferde kommt es aufgrund einer Überempfindlichkeitsreaktion auf Insektenspeichel, der beim Saugakt übertragen wird, zu klinischen Symptomen wie z.B. Juckreiz, Alopezie und Hautläsionen. Dies führt zu einer Gebrauchsminderung der betroffenen Pferde bis zu 50% während der Flugzeiten der Insekten von ca. März bis Oktober. Zusätzlich haben diese Pferde einen hohen Leidensdruck. Die Behandlung der Erkrankung ist sehr individuell und alle Therapien sind lediglich Versuche, auf die jedes betroffene Pferd anders anspricht. Sie bewirken teilweise eine Reduzierung der klinischen Symptome, doch gibt es derzeit keine Heilung für das SE. Diese Arbeit basiert auf einem neuartigen Therapieansatz für das Sommerekzem beim Pferd. Es wurde das als Therapeutikum bei menschlichen Autoimmunerkrankungen bekannte TACI-Ig für das Pferd entwickelt. Damit sollen die Zytokine BAFF und APRIL, die wichtige Regulatoren für die Reifung, Funktion und das Überleben von B-Zellen sind, gebunden werden um deren Wirkung auf die B-Zellen zu neutralisieren. Dadurch wird die Apoptoserate der B-Zellen erhöht. Die Reifung der B-Zellen zur Plasmazellen bleibt aus und es werden keine Immunglobuline produziert. Das wiederum verhindert die Freisetzung von Entzündungsmediatoren aus Mastzellen. Mit dem equinen TACI-Ig (eTACI-Ig) soll auf das Immunsystem des Pferdes eingewirkt werden, um die relevanten Reaktionsmechanismen für die Entstehung und Unterhaltung des Sommerekzems zu beeinflussen und damit den Ausbruch der Erkrankung zu verhindern. Für die Entwicklung des eTACI-Igs wurde der extrazelluläre Teil des equinen TACI aus der DNA des Pferdes herausamplifiziert und an einen FC-Teil eines equinen Immunglobulins gebunden. Im Anschluss wurde die Proteinbiosynthese von eTACI-Ig durchgeführt. Das nun vorliegende Protein wurde in einem in vitro Test-System auf seine Bindungsfähigkeit geprüft. Dafür wurden die equinen Zytokine eBAFF und eAPRIL produziert. Mit der Hilfe dieser beiden Zytokine konnte eine Bindung an eTACI- Ig nachgewiesen werden und liefert damit den Beweis für die Funktionsfähigkeit von TACI-Ig. In dem erfolgten ELISA konnte demnach bewiesen werden, dass das entwickelte eTACI-Ig an eBAFF und eAPRIL bindet, womit die Funktionalität des eTACI-Ig in vitro nachgewiesen wurde. Ziel dieses Projektes war es mit Hilfe der Kenntnissen zum Immunsystem des Pferdes und zum Krankheitsmechanismus des Sommerekzems, eine neuartige Therapie durch eTACI-Ig zu entwickeln und damit einer Linderung und/ oder Heilung des Sommerekzems zu forcieren. Um die richtige Funktionsweise der Therapie im lebenden Organismus zu verifizieren, müssen jedoch einige Vorversuche ausgeführt werden. Es empfehlen sich ex-vivo Tests, also Testreihen mit frischem Pferdeblut um eine Wirkung des eTACI-Igs auf die verschiedenen Zellen (z.B. B-Zellen, Plasmazellen) und die Immunglobuline zu untersuchen. Auch müssen Analysen stattfinden, die Einblick auf Wirksamkeit, Verträglichkeit und Dosierung des eTACI-Ig im Pferd geben. Trotz der Schwierigkeiten und hohen Kosten der Produktion von großen Mengen eTACI-Ig zur Behandlung des Sommerekzems sind finale Tests im Pferd nötig. Für die Zukunft könnte das eTACI-Ig in der Pferdemedizin für den Einsatz beim Sommerekzem ein interessantes Medikament werden, denn es lässt auf eine Therapie mit Aussicht auf Heilung hoffen, wodurch vielen betroffenen Pferden ein normales und unbeschwertes Pferdeleben ermöglicht werden könnte und vielleicht lässt es sich für weitere allergisch bedingte Erkrankungen beim Pferd einsetzten., Summer eczema in horses represents a seasonal recurrent allergic dermatitis to the insect’s salivary proteins of Culicoides biting midges. Clinical symptoms of affected horses include itching, alopecia and skin lesions, resulting in a diminished usability of up to 50% during the flight time of the insect from March to October. In addition, horses with summer eczema suffer from a lot of strain. Therapeutical treatment can be very individualans all therapies are approach only and every horse can react distinctly. State of the art therapy can only reduce clinical symptoms, yet a cure of summer eczema is still to be found. This work is thought to found a new therapeutical approach for the treatment of summer eczema in horse. On the basis of a therapeutical called TACI-Ig used to remedy human autoimmune diseases a strategy was developed to transfer the effective mechanism to the equine model. TACI-Ig neutralizes its pro-inflammatory cytokine ligands BAFF and APRIL, resulting in impaired maturation, functioning and survival of B cells, increases the apoptosis rate of these cells and thereby inhibiting their development into B cells as well as the consecutive production of immunoglobulins. As a result, no inflammatory molecules will be released from mast cells. A systemic administration of equine TACI-Ig (eTACI-Ig) could inhibit mechanisms relevant for development and sustentation of this disease. In this study eTACI-Ig was developed via PCR amplificationthe of the extracellular part of TACI from horse DNA and coupling it to the FC region of an equine immunoglobulin. The resulting fusion protein eTACI-Ig was tested for functionality by means of neutralizing its ligands equine BAFF and APRIL, which were also produced in the context of this work. ELISA tests clearly showed binding of eTACI-Ig to eBAFF and eAPRIL, proving the functionality of the newly synthesized fusion protein in vitro. Goal of this project was to transfer knowledge of the immune system of horses and the disease mechanisms to an effective approach for therapeutical treatment and potential cure of summer eczema by eTACI-Ig. Further ex and in vivo functionality tests are needed, e.g. the ex vivo study of its impact on various cell types and equine immunoglobulins on the base of fresh horse blood. Additionally, in vivo efficacy, dose responses and tolerance need to be determined. Although, production of big amounts of TACI-Ig can be difficult and expensive, its necessary in order to finally treat summer eczema systemically in horses. A successful treatment of summer eczema with eTACI-Ig could potentially give rise to treatment and curation of other allergic illnesses in horses and would be a fundamental break-through in horse medical science.
- Published
- 2014
29. [Radio- and photosensitization of plasmid DNA by DNA binding ligand propidium iodide: Investigation of Auger electron induction and detection of Cherenkov-emission].
- Author
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Kotzerke J, Runge R, Götze P, Wunderlich G, Enghardt W, and Freudenberg R
- Subjects
- Electrons, Ligands, DNA metabolism, Photosensitizing Agents metabolism, Photosensitizing Agents pharmacology, Plasmids genetics, Propidium metabolism, Propidium pharmacology, Radiation Tolerance drug effects
- Abstract
Purpose: We investigated whether propidium iodide (PI) enhances DNA damaging effects of ionizing and non-ionizing radiation species (X-rays, alpha-, beta-, auger electron emission and light of various wavelengths, respectively). This biophysical experimental setting allowed us, furthermore, to investigate whether Cherenkov emission can be detected by photodynamic effects and increased DNA damage., Material and Methods: Conformation changes of plasmid DNA were detected and quantified by gelelectrophoresis and fluorescence imaging. Hydrogen peroxide, stannous dichloride, and dimethylsulfoxide were used as chemical modulators, Tc-99m, Re-188, Ra-223, and x-ray (32 kV and 200 kV) reflected radiotoxicity and light (λ = 254 nm, 366 nm and 530-575 nm) induced phototoxicity., Results: Radiotracers and x-rays induced dose dependent DNA damage. PI did not serve as radiosensitizer in radioisotopes, while a low effect was detected in X-rays. The phototoxicity was dependent on the wavelengths of light. Light with a wavelength range of 530-575 nm in combination with PI resulted in direct DNA damage. The yield of Cherenkov emission was far below the photon emission of light irradiation and not distinguishable from general radiotoxicity., Conclusions: PI binds to plasmid DNA, is not chemotoxic, and increases radiotoxicity only to minor extent. Phototoxicity and its stimulation by PI is dependent on the wavelength of the light. No kind of energy deposition was capable of inducing an Auger electron cascade. Furthermore, no increase in DNA damage induced by photodynamic effects from Cherenkov emission was detectable., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2019
- Full Text
- View/download PDF
30. [Computer-aided design of selective ligands binding to G protein-coupled receptors]
- Author
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D, Schmidt and P, Kolb
- Subjects
Models, Molecular ,Binding Sites ,Models, Chemical ,Drug Design ,Computer Simulation ,Ligands ,Drug Therapy, Computer-Assisted ,Protein Binding ,Receptors, G-Protein-Coupled - Published
- 2013
31. Structure of selenium tetrafluoride: new pentafluor orthochalcogenates
- Author
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Seppelt, K
- Published
- 1975
32. Magnetochemical and spectroscopical studies on organo-metallic actinoid complexes
- Author
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Aderhold, C
- Published
- 1973
33. [α -Adrenoceptors: three subtypes for a broad spectrum of activity]
- Author
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Ralf, Gilsbach, Sebastian, Preissl, and Lutz, Hein
- Subjects
Sympathetic Nervous System ,Receptors, Adrenergic, alpha-2 ,Animals ,Humans ,Ligands ,Signal Transduction - Published
- 2011
34. Expanding the Catalytic Repertoire of DNAzymes by Modified Nucleosides
- Author
-
Marcel Hollenstein
- Subjects
Aptamer ,Molecular Sequence Data ,Oligonucleotides ,Deoxyribozyme ,Dnazymes ,Base-modified dna ,Ligands ,Biochemistry ,Modified nucleosides ,Catalysis ,Enzyme-mimetic ,Catalytic Domain ,Nucleic Acids ,QD1-999 ,Base Sequence ,Phenol ,biology ,Chemistry ,Oligonucleotide ,Active site ,Nucleosides ,DNA, Catalytic ,Mercury ,General Medicine ,General Chemistry ,Selex ,Combinatorial chemistry ,Kinetics ,Models, Chemical ,Organocatalysis ,biology.protein ,Nucleic acid ,RNA ,Nucleoside triphosphates ,Dinucleoside Phosphates - Abstract
Modified nucleoside triphosphates (dNTPs) are a versatile platform for the generation of high-density functionalized nucleic acids. The enzymatic polymerization of dNTPs allows the introduction of sensible functionalities that might not be compatible with the standard automated synthesis of oligonucleotides. Their application to in vitro selections, an elegant chemical approach to Darwinian evolution, delivers modified aptamers and catalytic nucleic acids with potentially enhanced properties. This review article highlights some recent synthetic examples of dNTPs bearing functionalities that are either found in the active site of protein enzymes or have been employed in organocatalysis and further underscores their usefulness in the development of some modified catalytic nucleic acids with special emphasis on M2+-independent RNA-cleaving DNAzymes.
- Published
- 2011
35. Applications of oxazoline and thiazoline ligands in asymmetric catalysis
- Author
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Maurer, Frauke and Kazmaier, Uli
- Subjects
ligands ,mechanism ,Ligand ,Thiazoline ,Diarylmethanole ,Zink ,Iridium ,ddc:540 ,Dihydrooxazole ,Mechanismus ,Rhodium ,Katalytische Hydrierung ,ddc:620 ,hydrogenation ,oxazoline - Abstract
Im Rahmen dieser Arbeit wurden chirale Oxazoline und Thiazoline auf ihre Eigenschaften als Liganden in der Zink-vermittelten asymmetrischen Katalyse geprüft. Die Untersuchungen bezogen sich auf Additionen an Aldehyde und Ketone sowie Reformatsky- und Imino-Reformatsky-Reaktionen. Im ersten Fall konnten mit dem verwendeten Thiazolin exzellente Selektivitäten festgestellt werden und mit einem modularen Konzept beide Enantiomeren einer Verbindung erhalten werden. Die Reformatsky- und Imino-Reformatsky-Reaktionen liefen in moderaten Ausbeuten und Selektivitäten ab. Im Anschluss wurden die Oxazoline und Thiazoline in Iridium- sowie Rhodium-Katalysatoren mit den entsprechenden P,N-Liganden überführt. Die Entwicklung eines kombinatorischen Systems ermöglichte die Testung der neuen Katalysatoren in der asymmetrischen Hydrierung. Das beste Oxazolin-Iridium-Derivat zeigte nahezu perfekte Umsätze und Selektivitäten in der Hydrierung von alpha,beta-ungesättigten Ketonen, wohingegen mit den Thiazolin-Analoga schlechtere Ergebnisse erzielt wurden. Alle Rhodium-Katalysatoren waren in den durchgeführten Hydrierungen unselektiv. Durch die Isolierung eines Monohydrido-Komplexes aus der Hydrierung eines Enamids konnte ein plausibler Reaktionsmechanismus postuliert werden. Schließlich wurden die Katalysatoren erfolgreich in der Hydrierung von Enamidoestern und alpha-Methylzimtsäureamiden eingesetzt. In the course of this work, chiral oxazolines as well as thiazolines have been used as catalysts in asymmetric zink-mediated transformations. In the investigations towards the arylation of aldehydes and ketones the used thiazoline showed very good selectivities. Via a modular approach, both of the possible enantiomers could be obtained. The Reformatsky- and Imino-Reformatsky-reactions gave moderate yields and enantio-selectivities. Moreover, the oxazolines and thiazolines have been converted into P,N-ligated iridium and rhodium-complexes. In a developed combinatory system, the new complexes could be evaluated towards their properties as catalysts in asymmetric hydrogenations. The best oxazoline-iridium-derivative showed nearly perfect conversions and selectivities in the hydrogenation of alpha,beta-unsaturated ketones, whereas the thiazoline-analogs achieved worse results. All synthesized rhodium complexes showed no activity in the performed hydrogenations. Via the isolation of a monohydrido complex from the hydrogenation of an enamide, a plausible reaction mechanism could be postulated. Finally, the complexes could be successfully employed in the hydrogenation of enamido esters and alpha-methyl cinnamic acid amides.
- Published
- 2011
- Full Text
- View/download PDF
36. [Causes of selectivity, activation and inhibition. Molecular mechanisms of endothelin-receptor recognition]
- Author
-
Jens, Lättig and Gerd, Krause
- Subjects
Endothelin Receptor Antagonists ,Models, Molecular ,Sulfonamides ,Receptors, Endothelin ,Molecular Sequence Data ,Humans ,Bosentan ,Amino Acid Sequence ,Isoxazoles ,Thiophenes ,Ligands ,Antihypertensive Agents - Published
- 2010
37. The Metal-Thiolate Clusters of Plant Metallothioneins
- Author
-
Eva Freisinger, University of Zurich, and Freisinger, Eva
- Subjects
10120 Department of Chemistry ,Models, Molecular ,Spectrometry, Mass, Electrospray Ionization ,Cations, Divalent ,Protein Conformation ,Molecular Sequence Data ,1600 General Chemistry ,010402 general chemistry ,Ligands ,01 natural sciences ,Bioinorganic chemistry ,Metal ,Mice ,Species Specificity ,540 Chemistry ,Animals ,Humans ,Lmct bands ,Amino Acid Sequence ,Sulfhydryl Compounds ,QD1-999 ,Spectroscopy ,Plant Proteins ,Plant metallothioneins ,010405 organic chemistry ,Chemistry ,General Medicine ,General Chemistry ,0104 chemical sciences ,3. Good health ,Plant metallothionein ,Rats ,Evolutionary biology ,Metals ,visual_art ,visual_art.visual_art_medium ,Metallothionein ,Sequence Alignment ,Metal-thiolate cluster ,Protein Binding - Abstract
While structures of mammalian metallothioneins and their metal-thiolate clusters have been known for nearly 20 years, the first three-dimensional structure of a plant metallothionein was only published very recently. Also in other aspects, research on plant metallothioneins lags behind what is known about the vertebrate forms. However, in the past years more and more information, mostly based on experiments performed with optical spectroscopy has become available and permit sometimes unforeseen insights. In the following, the different experimental strategies applied in our laboratory will be described together with the progress we have made over the past years in detecting and characterizing the metal-thiolate clusters of plant metallothioneins.
- Published
- 2010
38. [Natural and synthetic glycosaminoglycans. Molecular characteristics as the basis of distinct drug profiles]
- Author
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S, Alban
- Subjects
Structure-Activity Relationship ,Heparin ,Polysaccharides ,Thromboembolism ,Anticoagulants ,Humans ,Heparin, Low-Molecular-Weight ,Ligands ,Antithrombins ,Factor Xa Inhibitors ,Glycosaminoglycans - Abstract
For several decades, anticoagulants based on glycosaminoglycans (GAG) are drugs of choice in the therapy and prophylaxis of thromboembolic diseases. In principle, it has to be differentiated between the natural GAG-anticoagulants, which are molecular mixtures with complex composition, and the synthetic GAG-anticoagulants, which are chemically defined oligosaccharides. The former include unfractionated heparin, the various low molecular weight heparins and danaparoid. Representatives of the second group are fondaparinux, idraparinux and the hexadecasaccharide SR123781A. They share a common mechanism of action together with the endogenous antithrombotic heparan sulfate, i.e. the catalysis of the antithrombin-mediated inhibition of factor Xa. Besides, considerable structural differences between the various GAG-anticoagulants result in rather distinct product characteristics. This concerns their pharmacodynamics, pharmacokinetics as well as practice-related aspects such as dosage, monitoring, accumulation tendency, antagonisation and HIT-Typ II.
- Published
- 2008
39. [Cytomics and receptor interaction]
- Author
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Gero, Brockhoff
- Subjects
Enzyme Activation ,ErbB Receptors ,Neoplasms ,Gene Amplification ,Humans ,Receptor Protein-Tyrosine Kinases ,Receptor Cross-Talk ,Ligands ,Biology ,Models, Biological ,Cell Division - Abstract
The system of erbB-receptor-tyrosine-kinases (RTKs) appears considerable complex because four erbB-receptors crossactivate each other via homo- and heterointeraction upon ligand binding. This complexicity is additionally elevated by scores of corresponding growth factors with unique binding- and activation-specificity. The total receptor-ligand system provides the basis for intracellular signal- diversity and -specificity. Significant oncological importance is attributed to the family of erbB-RTKs, which are known to cause and contribute to carcinogenesis, tumor progression, invasion, metastasis, e. g. based on uncontrolled cell growth and cell proliferation. The detection of erbB-receptor gene amplification or corresponding protein overexpression is well established in tumor diagnosis and an essential element for therapy decision. However, the assessment of the coexpression profile of erbB-receptors and the presence or absence of growth factors has not been implemented into pathological diagnosis so far. Cytomics represents a novel discipline in systems-biology. It is dedicated to understand and resolve biocomplexicity of cells, cellular components, and cell-systems. Understanding the function of the integrated erbB-receptor-system on a cytomic level will facilitate to more precisely follow-up the course of disease and thereby to elevate prognosis to the level of individual prediction. A system biological approach should involve the analysis of molecular function and dynamics on a single cell level and thereby is expected to characterize the disease in terms of a given molecular equivalent. Additionally, new and highly specific drug targets are likely to be identified. The comprehensive analysis of the complex molecular erbB-receptor system will enable to stratify tumor patients more precisely and simultaneously to specify erbB-receptor based therapeutic strategies in terms of individualized medicine.
- Published
- 2007
40. Synthese von amphiphilen unimolekularen Mizellen als Liganden zur Hydroformylierung in wässrigen Medien
- Author
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West, Nuki, Nuyken, Oskar (Prof. Dr.), Nitsch, Walter (Prof. Dr.), and Gemmecker, Gerd (Priv.-Doz. Dr.)
- Subjects
Mizellen ,Liganden ,Hydroformylierung ,ddc:540 ,Micelles ,ligands ,hydroformylation ,Chemie - Abstract
Ziel der Arbeit war es wasserlösliche Liganden zu synthetisieren um eine Hydroformylierung in wässrigen Systemen zu ermöglichen. Gelöst wurde diese Aufgabe durch Bereitstellung von Kern-Schale-Polymeren, wobei der Kern hydrophob und die Schale hydrophil gewählt wurde. Als Liganden wurden Triphenylphospaneinheiten gewählt und an der Kernoberfläche kovalent fixiert. Es konnte gezeigt werden, dass die so dargestellten Systeme eine Hydroformylierung in wässrigen Systemen ermöglichen, und dass die Produkte hohe n/iso Verhältnisse aufweisen. The major aim was to provide water soluble ligands in order to enable hydroformylation reactions in aqueous media. This could be solved by providing core-shell polymers comprising a hydrophobic core and a hydrophilic shell. The ligand moieties were triphenylphosphine derivates which were covalently bonded to the surface of the core. It could be shown, that the provided systems were capable of enabling hydroformylation reactions in aqueoous media, and that the obtained products had a high n/iso ratio.
- Published
- 2007
41. [Current insights into the development of new glucocorticoid receptor ligands]
- Author
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F, Buttgereit, I-H, Song, R H, Straub, and G-R, Burmester
- Subjects
Arthritis, Rheumatoid ,Drug Delivery Systems ,Receptors, Glucocorticoid ,Drug Design ,Anti-Inflammatory Agents ,Humans ,Ligands ,Glucocorticoids - Abstract
Recent insights into the mechanisms of genomic and non-genomic glucocorticoid actions have stimulated the search for novel glucocorticoid receptor ligands. These efforts are driven by the need to improve the benefit-risk ratio of these important drugs. Glucocorticoids are very frequently and successfully used drugs which mediate important immunosuppressive and anti-inflammatory effects, but unfortunately they have pleiotropic effects causing a number of adverse reactions which limit their clinical use, especially at higher dosages and for longer periods. For this reason, novel glucocorticoid receptor ligands are being developed, among them selective glucocorticoid receptor agonists (SEGRAs). SEGRAs are drugs that predominantly induce transrepression effects (inhibition of protein synthesis), whereas the transactivation activity (induction of protein synthesis) is significantly reduced as compared with conventional glucocorticoid drugs. This makes sense since it became evident over the last few years that many adverse effects are predominantly caused by the transactivation mechanism, whereas anti-inflammatory effects are mostly mediated by transrepression mechanisms. Other interesting examples for exciting new developments are NO-glucocorticoids and long-circulating liposomal glucocorticoids. It is, however, true of all these developments that further in vivo and in vitro investigations and clinical trials will have to define in more detail their safety-efficacy profile in order to answer the questions whether these drugs as "improved glucocorticoids" will enter clinical medicine in the near future.
- Published
- 2005
42. [Lutetium-177-PSMA radioligand therapy : Consensus within the framework of GKV-funded care between the university hospitals in Aachen, Bonn, Düsseldorf, Essen, and Cologne and the MDK Nordrhein].
- Author
-
Ahmadzadehfar H, Albers P, Bockisch A, Boegemann M, Böhme C, Burchert W, Dietlein M, Drzezga A, Fabry U, Feldmann G, Heidenreich A, Heinzel A, Herrmann K, Heyll A, Höhling C, Kreuzer C, Laufer D, Mengel R, Mottaghy FM, Müller HW, Müller SC, Ost E, Rahbar K, Reifenhäuser W, Schäfers M, Schlenkhoff C, Schmidt M, Schmidt-Wolf I, Wildenhain C, Zimmer B, and Essler M
- Subjects
- Antigens, Surface, Consensus, Germany, Hospitals, University, Humans, Ligands, Lutetium adverse effects, Lutetium economics, Male, Prostatic Neoplasms, Castration-Resistant metabolism, Radioisotopes adverse effects, Radioisotopes economics, Treatment Outcome, Health Care Costs, Insurance, Health, Insurance, Health, Reimbursement, Lutetium therapeutic use, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant radiotherapy, Radioisotopes therapeutic use
- Abstract
In the last 3 years, Lutetium-177 prostate-specific membrane antigen radioligand therapy (Lu-177-PSMA-RLT) has received increasing attention in nuclear medicine as a new form of treatment for castration-resistant metastatic prostate cancer. This therapy combines the radionuclide Lutetium-177, which has been therapeutically used in nuclear medicine for many years, with a molecular target of the transmembrane prostate-specific membrane antigen expressed by prostate cancer cells. Since there are no prospective randomized studies on Lu-177-PSMA-RLT and the question of reimbursement has repeatedly been the subject of review by the MDK Nordrhein (Medischenische Dienst der Krankenversicherung), there was a desire because of the increasing number of patients being treated to clarify under which circumstances Lu-177-PSMA-RLT can be reimbursed by German statutory health insurance. The goals of this article are to help treating physicians understand how this new therapy option works, to integrate it in the overall therapy concept for castration-resistant metastatic prostate cancer, and, above all, to use Lu-177-PSMA-RLT-based on the current data-at the right place in the therapy sequence of castration-resistant metastatic prostate cancer.
- Published
- 2018
- Full Text
- View/download PDF
43. [Kit-based radiolabeling of PSMA ligands].
- Author
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Derlin T
- Subjects
- Humans, Prostatic Neoplasms, Ligands, Radiopharmaceuticals
- Published
- 2018
- Full Text
- View/download PDF
44. [Expression of osteoclast stimulating and differentiating factors in a murine model of localized inflammatory bone resorption]
- Author
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H, Sudhoff, Y, Liebehenz, J, Aschenbrenner, S, Euteneuer, J, Ebmeyer, M, Bernal-Sprekelsen, T, Stark, and S, Dazert
- Subjects
Male ,Cholesteatoma, Middle Ear ,Macrophage Colony-Stimulating Factor ,Osteoprotegerin ,Osteoclasts ,Receptors, Cytoplasmic and Nuclear ,Skin Transplantation ,Ligands ,Immunohistochemistry ,Transplantation, Autologous ,Receptors, Tumor Necrosis Factor ,Mice, Inbred C57BL ,Disease Models, Animal ,Mice ,Microscopy, Electron, Scanning ,Animals ,Bone Resorption ,Glycoproteins - Abstract
The pathology associated to cholesteatoma is predominantly a consequence of osteoclast-mediated bone resorption within the middle ear. To assess its pathogenesis a murine model for dermal-implant induced osteolysis was evaluated for the expression of osteoclast stimulating and differentiating factors.Mouse calvaria were analysed for the expression of osteoprotegerin ligand (OPGL), osteoprotegerin (OPG) and macrophage-colony stimulating factor (M-CSF) using immunohistochemistry. The detection of osteoclast cell lineage was acquired by immunohistochemistry using markers CD 4, CD 11a, CD 11b, CD 14, CD 51, CD 68 and TRAP.An increased expression of the investigated cytokines M-CSF, OPG and OPGL was demonstrated by immunohistochemistry. The presence of osteoclast precursor cells and mature resorbing osteoclasts was confirmed in time-dependent manner triggered by dermal implantation.This study reveals the basic events in osteoclast biology in localized inflammatory bone resorption and provides new insights into the comprehension of cholesteatoma-induced bone resorption.
- Published
- 2004
45. First tervalent thorium in an aromatic complex: tris(cyclopentadienyl)thorium(III)
- Author
-
Baumgaertner, F
- Published
- 1974
46. Complexometric behavior of some 2-mercapto-p-cresols. I
- Author
-
Reiterer, H
- Published
- 1975
47. High tension electrophoretic separation of inorganic ions with special consideration of the platinum metals. V
- Author
-
Zeitler, G
- Published
- 1975
48. [What takes place in the receptor? Ligand-receptor interaction in 5-HT agonists]
- Author
-
Marion, Gurrath
- Subjects
Structure-Activity Relationship ,Models, Chemical ,Migraine Disorders ,Receptors, Serotonin ,Animals ,Humans ,Ligands ,Serotonin Receptor Agonists - Published
- 2002
49. CONSTITUTION AND STABILITY OF THE CHELATES FORMED BY QUINQUEVALENT NEPTUNIUM WITH N-2-HYDROXYETHYLIMINODIACETIC ACID.
- Author
-
Wede, U
- Published
- 1969
50. STABILITY CONSTANTS OF Np(V) ION COMPLEXES WITH $alpha$-HYDROXYCARBOXYLIC ACIDS.
- Author
-
Schaefer, J
- Published
- 1969
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