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Introduction: Tumor burden is a frequently mentioned parameter; however, a commonly accepted definition is still lacking., Methods: In this double-center prospective and retrospective study, 76 patients with unresectable stage III or stage IV melanoma treated with ipilimumab were included. We defined the baseline tumor burden (BTB) as the global sum of all metastases' longest diameters before treatment started and correlated the calculated BTB with disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and with the baseline levels of LDH, S100B, and sULPB2., Results: BTB correlated significantly with DCR (p = 0.009), PFS (p = 0.002), OS (p = 0.032), and the occurrence of NRAS mutation (p = 0.006). BTB was also correlated to baseline serum levels of LDH (p = 0.011), S100B (p = 0.027), and SULBP (p < 0.0001). Multivariate analysis revealed that BPB and LDH were independently correlated with PFS and OS. With increasing BTB, disease control was less likely; no patient with a BTB >200 mm achieved disease control. For patients with brain metastasis, no correlation of BTB with DCR (p = 0.251), PFS (p = 0.059), or OS (p = 0.981) was observed., Conclusion: Calculated BTB is an independent prognostic factor for patients with metastatic melanoma treated with ipilimumab. Using calculated BTB as a definition of tumor burden may help increase comparability of outcome of therapies in future studies., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Onychomycosis affects up to 50% of patients in the older population., Objectives: This study aimed to explore heat sensitivity of Trichophyton rubrum and Trichophyton interdigitale as pathogens of onychomycosis., Materials & Methods: The fungi were heated in sterile saline solution up to 100°C for five or 10 minutes with or without additional previous treatment with 1% ciclopirox solution or chitinase and 1,3 -galactidase or for 45 minutes at 40°C or 60°C with washing powder. Subsequently, the fungi were cultured and regrowth was assessed after one week., Results: After heating T. rubrum for five minutes at 60°C, growth was completely inhibited. After heating T. interdigitale for five minutes at 60°C, all of the samples regrew, and at 95°C, none of the samples regrew. No difference between five and 10-minute heating was observed. Previous incubation with 1% ciclopirox solution for 24 hours inhibited the growth of T. rubrum completely. T. interdigitale was still able to regrow to 100% after five minutes at 40°C, to 33% after 60°C, and to 22% after 80°C. Incubation for 45 minutes with washing powder solution at 40°C or 60°C did not lead to significant growth reduction of T. rubrum or interdigitale. Two hours incubation with -1,3-glucanase and chitinase prior to five minutes of heating to 60°C and 80°C reduced the heat resistance of T. interdigitale; growth was inhibited in 56% and 100% of the samples, respectively., Conclusion: The heat resistance of T. rubrum and interdigitale should be considered using non-medical thermal treatment.

Multidrug-resistant (MDR) bacteria is a severe threat to public health. Therefore, it is urgent to establish effective screening systems for identifying novel antibacterial compounds. In this study, a highly miniaturized droplet microarray (DMA) based high-throughput screening system is established to screen over 2000 compounds for their antimicrobial properties against carbapenem-resistant Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA). The DMA consists of an array of hydrophilic spots divided by superhydrophobic borders. Due to the differences in the surface wettability between the spots and the borders, arrays of hundreds of nanoliter-sized droplets containing bacteria and different drugs can be generated for screening applications. A simple colorimetric viability readout utilizing a conventional photo scanner is developed for fast single-step detection of the inhibitory effect of the compounds on bacterial growth on the whole array. Six hit compounds, including coumarins and structurally simplified estrogen analogs are identified in the primary screening and validated with minimum inhibition concentration assay for their antibacterial effect. This study demonstrates that the DMA-based high-throughput screening system enables the identification of potential antibiotics from novel synthetic compound libraries, offering opportunities for development of new treatments against multidrug-resistant bacteria., (© 2022 The Authors. Advanced Biology published by Wiley-VCH GmbH.)

Human pluripotent stem cells (hPSCs) hold great promise for applications in cell therapy and drug screening in the cardiovascular field. Bone morphogenetic protein 4 (BMP4) is key for early cardiac mesoderm induction in hPSC and subsequent cardiomyocyte derivation. Small-molecular BMP4 mimetics may help to standardize cardiomyocyte derivation from hPSCs. Based on observations that chalcones can stimulate BMP4 signaling pathways, we hypothesized their utility in cardiac mesoderm induction. To test this, we set up a two-tiered screening strategy, (1) for directed differentiation of hPSCs with commercially available chalcones (4'-hydroxychalcone [4'HC] and Isoliquiritigen) and 24 newly synthesized chalcone derivatives, and (2) a functional screen to assess the propensity of the obtained cardiomyocytes to self-organize into contractile engineered human myocardium (EHM). We identified 4'HC, 4-fluoro-4'-methoxychalcone, and 4-fluoro-4'-hydroxychalcone as similarly effective in cardiac mesoderm induction, but only 4'HC as an effective replacement for BMP4 in the derivation of contractile EHM-forming cardiomyocytes., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Aldosterone 1 is a mineralocorticoid, it has great influence on the blood pressure and its glucuronide is an important marker for the detection of several diseases. Here, we describe the chemical synthesis of different aldosterone-18- and 20-glucuronides. Reaction of trimethylsilyl 2,3,4-tri- acetyl-1-β-glucuronic acid methyl ester 5 b and aldosterone diacetate 11 in the presence of TMSOTf gave the 18-α-glucuronide 9 a. The 18-β-glucuronide 15 b and the 20-β-glucuronide 16 b could be obtained by reaction of methyl 2,3,4-tri-O-isobutyryl-1α-glucuronate trichloroacetimidate 14 and aldosterone 21-acetate 8 in the presence of TMSOTf or BF 3 ⋅OEt 2 . Finally, reaction of aldosterone 21-acetate 8 and methyl 2,3,4-triacetyl-1α-glucuronate trichloroacetimidate 19 in the presence of TMSOTf gave the corresponding methyl 18-β-triacetylglucuronate 9 b, which was transformed into the desired aldosterone-18-β-glucuronide 3 by two enzyma- tic transformations., (© 2020 Wiley-VCH GmbH.)

Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase, and this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesized that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole-body irradiation treatment of mice. Moreover, taking advantage of a mouse model of adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD prodrug selectively reduced the number of β-catenin-positive preneoplastic senescent cells. In summary, the above results make a case for testing the potential of galactose-modified duocarmycin prodrugs to treat senescence-related pathologies., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Bifunctional duocarmycin analogues are highly cytotoxic compounds that have been shown to be irreversible aldehyde dehydrogenase 1 inhibitors. Interestingly, cells with low aldehyde dehydrogenase 1 expression are also sensitive to bifunctional duocarmycin analogues, suggesting the existence of another target. Through in silico approaches, including principal component analysis, structure-similarity search, and docking calculations, protein tyrosine kinases, and especially the vascular endothelial growth factor receptor 2 (VEGFR-2), were predicted as targets of bifunctional duocarmycin analogues. Biochemical validation was performed in vitro, confirming the in silico results. Structural optimization was performed to mainly target VEGFR-2, but not aldehyde dehydrogenase 1. The optimized bifunctional duocarmycin analogue was synthesized. In vitro assays revealed this bifunctional duocarmycin analogue as a strong inhibitor of VEGFR-2, with low residual aldehyde dehydrogenase 1 activity. Altogether, studies revealed bifunctional duocarmycin analogues as a new class of naturally derived compounds that express a very high cytotoxicity to cancer cells overexpressing aldehyde dehydrogenase 1 as well as VEGFR-2.

A one pot borylation/Suzuki-Miyaura reaction of the 4-bromochromanone lactones 21 and 23, respectively, followed by cleavage of the methyl ether moieties gave the homodimeric chromanone lactones 10 and 11. Reaction of a 1:1 mixture of 21 and 23 under otherwise identical conditions gave a 1:1:2-mixture of the two homodimers 10 and 11 and the heterodimer 12. This is the first example of the preparation of a heterodimeric chromanone lactone. For the enantioselective synthesis of the starting material, phenol 17 was transformed into the chromane 18 using a Wacker-type cyclisation with 99 % ee and 80 % yield., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This work reports on the enantioselective total synthesis of the two dimeric natural chromanone lactones phomopsis-H76 A (5) and blennolide H (6). Both syntheses could be achieved from chromane 11, which was obtained by an enantioselective Wacker-type cyclization with >99 % ee. The dimerization of the corresponding monomers was performed using a palladium-catalyzed Suzuki reaction. Moreover, within this work it was possible to revise the absolute configuration of phomopsis-H76 A and determine the relative as well as absolute configuration of blennolide H., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An enantioselective total synthesis of blennolide D and the enantiomers of blennolide E and F is described using an enantioselective Wacker-type oxidation followed by the formation of the lactone moiety. For the introduction of the hydroxyl group in the γ-lactone, a TEMPO-mediated α-oxygenation was used which was followed by a benzylic oxidation and deprotection to give the desired compounds. In addition, an unknown diastereomer was synthesized.

A palladium-catalyzed 4-fold domino reaction consisting of two carbopalladation reactions and two C-H activation reactions, followed by the introduction of an acrylate moiety, led to the tetra-substituted helical alkene A2, using the dialkyne A3 as a substrate. The alkene was copolymerized with butyl acrylate by using the reversible addition-fragmentation chain transfer polymerization (RAFT) to give the desired polymeric switch A1.

The first enantioselective total synthesis of natural dicerandrol C (1 c) as its enantiomer containing a dimeric tetrahydroxanthenone skeleton is described starting from the enantiopure chromane 6 which was obtained through a Wacker-type cyclization with >99 % ee. For the formation of the dimeric skeleton a palladium-catalyzed Suzuki reaction was used. The synthesis allowed the confirmation of the absolute configuration of the dicerandrols., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The K v 10.1 (Eag1) voltage-gated potassium channel represents a promising molecular target for novel cancer therapies or diagnostic purposes. Physiologically, it is only expressed in the brain, but it was found overexpressed in more than 70 % of tumours of diverse origin. Furthermore, as a plasma membrane protein, it is easily accessible to extracellular interventions. In this study we analysed the feasibility of the anti-K v 10.1 monoclonal antibody mAb62 to target tumour cells in vitro and in vivo and to deliver therapeutics to the tumour. Using time-domain near infrared fluorescence (NIRF) imaging in a subcutaneous MDA-MB-435S tumour model in nude mice, we showed that mAb62-Cy5.5 specifically accumulates at the tumour for at least 1 week in vivo with a maximum intensity at 48 h. Blocking experiments with an excess of unlabelled mAb62 and application of the free Cy5.5 fluorophore demonstrate specific binding to the tumour. Ex vivo NIRF imaging of whole tumours as well as NIRF imaging and microscopy of tumour slices confirmed the accumulation of the mAb62-Cy5.5 in tumours but not in brain tissue. Moreover, mAb62 was conjugated to the prodrug-activating enzyme β-D-galactosidase (β-gal; mAb62-β-gal). The β-gal activity of the mAb62-β-gal conjugate was analysed in vitro on K v 10.1-expressing MDA-MB-435S cells in comparison to control AsPC-1 cells. We show that the mAb62-β-gal conjugate possesses high β-gal activity when bound to K v 10.1-expressing MDA-MB-435S cells. Moreover, using the β-gal activatable NIRF probe DDAOG, we detected mAb62-β-gal activity in vivo over the tumour area. In summary, we could show that the anti-K v 10.1 antibody is a promising tool for the development of novel concepts of targeted cancer therapy.

The recent discovery of c-Jun NH2-terminal kinase JNK1 suppression by natural quercetagetin (1) is a promising lead for the development of novel anticancer agents. Using both X-ray structure and docking analyses we predicted that 5'-hydroxy- (2) and 5'-hydroxymethyl-quercetagetin (3) would inhibit JNK1 more actively than the parent compound 1. Notably, our drug design was based on the active enzyme-ligand complex as opposed to the enzyme's relatively open apo structure. In this paper we test our theoretical predictions, aided by docking-model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3. As calculated, both compounds strongly suppress JNK1 activity. The IC50 values were determined to be 3.4 μM and 12.2 μM, respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC50 =4.6 μM). Compound 2 was also shown to suppress matrix metalloproteinase-1 expression with high specificity after UV irradiation., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first enantioselective synthesis of a secalonic acid containing a dimeric tetrahydroxanthenone skeleton is described, using a Wacker-type cyclization of a methoxyphenolic compound to form a chiral chroman with a quaternary carbon stereogenic center with >99% ee. Further steps are a Sharpless dihydroxylation and a Dieckmann condensation to give a tetrahydroxanthenone. A late-stage one-pot palladium-catalyzed Suzuki-dimerization reaction leads to the 2,2'-biphenol linkage to complete the enantioselective total synthesis of secalonic acid E in 18 steps with 8% overall yield., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Analogues of the natural product duocarmycin bearing an indole moiety were shown to bind aldehyde dehydrogenase 1A1 (ALDH1A1) in addition to DNA, while derivatives without the indole solely addressed the ALDH1A1 protein. The molecular mechanism of selective ALDH1A1 inhibition by duocarmycin analogues was unraveled through cocrystallization, mutational studies, and molecular dynamics simulations. The structure of the complex shows the compound embedded in a hydrophobic pocket, where it is stabilized by several crucial π-stacking and van der Waals interactions. This binding mode positions the cyclopropyl electrophile for nucleophilic attack by the noncatalytic residue Cys302, thereby resulting in covalent attachment, steric occlusion of the active site, and inhibition of catalysis. The selectivity of duocarmycin analogues for ALDH1A1 is unique, since only minor alterations in the sequence of closely related protein isoforms restrict compound accessibility., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A highly efficient palladium-catalyzed fourfold tandem-domino reaction consisting of two carbopalladation and two C-H-activation steps was developed for the synthesis of two types of tetrasubstituted alkenes 3 and 6 with intrinsic helical chirality starting from substrates 1 and 4, respectively. A sixfold tandem-domino reaction was also developed by including a Sonogashira reaction. 20 compounds with different substitution patterns were prepared with yields of up to 97 %. Structure elucidation by X-ray crystallography confirmed helical chirality of the two alkene moieties. Photophysical investigations of some of the compounds showed pronounced switching properties through light-controlled changes of their stereochemical configuration., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An enantioselective total synthesis of the natural (+)-linoxepin (1) was accomplished in eleven steps from bromovanin (24). Key steps are a domino carbopalladation/ Mizoroki-Heck reaction with the formation of a pentacyclic system, an asymmetric hydroboration as well as an oxidative lactonization., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A fast and efficient palladium-catalyzed fourfold domino Sonogashira/double-carbopalladation/CH-activation reaction that converts simple aromatic systems into complex polycyclic hydrocarbons has been developed. A number of substituted products has thus been prepared in yields up to 89 %. The structural assignment has been confirmed by using single-crystal X-ray crystallography. The products show intriguing fluorescence activity and thus might serve as chemical sensors or fluorescent imaging dyes., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first enantioselective total syntheses of the tetrahydroxanthenone (-)-blennolide C (ent-4) and related γ-lactonyl chromanone (-)-gonytolide C (ent-3) are reported. Key to the syntheses is an enantioselective domino-Wacker/carbonylation/methoxylation reaction to set up the stereocentre at C-4a. Various chiral BOXAX ligands were investigated, including novel (S,S)-iBu-BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The second stereocentre at C-4 was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)- and (DHQD)-based ligands enabled the preparation of both the anti-isomer 14 a and the syn-isomer 14 b in very good to reasonable selectivities of 13.7:1 and 1:3.7, respectively. While 14 a was further converted to ent-3 and ent-4, 14 b was elaborated to syn-acid 25 and 2'-epi-gonytolide C 28., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Blennolide A can be synthesized through an enantioselective domino-Wacker/carbonylation/methoxylation reaction of 7a with 96 % ee and an enantioselective Wacker oxidation of 7b with 89 % ee. Further transformations led to the α,β-unsaturated ester (E)-17, which was subjected to a highly selective Michael addition, introducing a methyl group to give 18a. After a threefold oxidation and an intramolecular acylation, the tetrahydroxanthenone 4 was obtained, which could be transformed into (-)-blennolide A (ent-1) in a few steps., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Conventional cancer chemotherapy is limited by systemic toxicity and poor selectivity. Tumor-selective activation of glucuronide prodrugs by beta-glucuronidase in the tumor microenvironment in a monotherapeutic approach is one promising way to increase cancer selectivity. Here we examined the cellular requirement for enzymatic activation as well as the in vivo toxicity and antitumor activity of a glucuronide prodrug of a potent duocarmycin analogue that is active at low picomolar concentrations. Prodrug activation by intracellular and extracellular beta-glucuronidase was investigated by measuring prodrug 2 cytotoxicity against human cancer cell lines that displayed different endogenous levels of beta-glucuronidase, as well as against beta-glucuronidase-deficient fibroblasts and newly established beta-glucuronidase knockdown cancer lines. In all cases, glucuronide prodrug 2 was 1000-5000 times less cytotoxic than the parent duocarmycin analogue regardless of intracellular levels of beta-glucuronidase. By contrast, cancer cells that displayed tethered beta-glucuronidase on their plasma membrane were 80-fold more sensitive to glucuronide prodrug 2, demonstrating that prodrug activation depended primarily on extracellular rather than intracellular beta-glucuronidase activity. Glucuronide prodrug 2 (2.5 mg/kg) displayed greater antitumor activity and less systemic toxicity in vivo than the clinically used drug carboplatin (50 mg/kg) to mice bearing human lung cancer xenografts. Intratumoral injection of an adenoviral vector expressing membrane-tethered beta-glucuronidase dramatically enhanced the in vivo antitumor activity of prodrug 2. Our data provide evidence that increasing extracellular beta-glucuronidase activity in the tumor microenvironment can boost the therapeutic index of a highly potent glucuronide prodrug.

For the synthesis of (-)-diversonol (ent-1), an enantioselective domino-Wacker/carbonylation/methoxylation reaction and an enantioselective Wacker oxidation were used to give the chroman in high yield and 96% and 93% ee, respectively. Dihydroxylation at the vinyl moiety using the Sharpless procedure and a Wittig-Horner reaction followed by hydrogenation, benzylic oxidation, and an intramolecular acylation provided the tetrahydroxanthenone, from which ent-1 is accessible in a few steps. Furthermore, the synthesis of the diastereomeric diversonol rac-1,9a-epi-diversonol (rac-41) is also described., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A main problem of common cancer chemotherapy is the occurrence of severe side effects caused by insufficient selectivity of the applied drugs. A possible concept to overcome this limitation is light-driven prodrug monotherapy. The synthesis as well as photochemical and biological evaluation of new photoactivatable prodrugs is described. Best results were obtained with prodrug (S,S)-7a. The photochemical labile protecting groups in (S,S)-7a can easily be removed by irradiation with UV-A light in 30 min with a power of only 2 J cm(-2). The determination of the in vitro cytotoxicity by using an HTCFA-test reveals a QIC(50) value of 8200 and the prodrug is more than two million times less cytotoxic than the corresponding seco-drug (-)-(S,S)-5 with an IC(50) value of about 110 fM. The big therapeutic window makes (S,S)-7a very suitable for its use in selective cancer therapy., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

For a better understanding of the mode of action of duocarmycin and its analogs, the novel fluorescent duocarmycin derivatives 13-15 and 17b-19b were synthesized, and their bioactivity as well as their cellular uptake investigated using confocal laser scanning microscopy (CLSM) in live-cell imaging experiments., (Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.)

The soil-borne fungal pathogen Verticillium longisporum causes vascular disease on Brassicaceae host plants such as oilseed rape. The fungus colonizes the root xylem and moves upwards to the foliage where disease symptoms become visible. Using Arabidopsis as a model for early gene induction, we performed root transcriptome analyses in response to hyphal growth immediately after spore germination and during penetration of the root cortex, respectively. Infected roots showed a rapid reprogramming of gene expression such as activation of transcription factors, stress-, and defense-related genes. Here, we focused on the highly coordinated gene induction resulting in the production of tryptophan-derived secondary metabolites. Previous studies in leaves showed that enzymes encoded by CYP81F2 and PEN2 (PENETRATION2) execute the formation of antifungal indole glucosinolate (IGS) metabolites. In Verticillium-infected roots, we found transcriptional activation of CYP81F2 and the PEN2 homolog PEL1 (PEN2-LIKE1), but no increase in antifungal IGS breakdown products. In contrast, indole-3-carboxylic acid (I3CA) and the phytoalexin camalexin accumulated in infected roots but only camalexin inhibited Verticillium growth in vitro. Whereas genetic disruption of the individual metabolic pathways leading to either camalexin or CYP81F2-dependent IGS metabolites did not alter Verticillium-induced disease symptoms, a cyp79b2 cyp79b3 mutant impaired in both branches resulted in significantly enhanced susceptibility. Hence, our data provide an insight into root-specific early defenses and suggest tryptophan-derived metabolites as active antifungal compounds against a vascular pathogen.

An efficient total synthesis of (+)-(R)-Pinnatolide is described. As a key step an asymmetric multicomponent domino allylation reaction of methyl levulinate is used to form the quaternary stereogenic center in a highly selective way.

Helical tetrasubstituted alkenes (7) were obtained in a highly efficient way through a palladium-catalyzed domino-carbopalladation/CH-activation reaction of propargylic alcohols 6 in good to excellent yields. Electron-withdrawing- and electron-donating substituents can be introduced onto the upper and lower aromatic rings. The substrates (6) for the domino process were synthesized by addition of the lithiated alkyne (20) to various aldehydes (19); moreover, the substrates were accessible enantioselectively (in 95% ee) by reduction of the corresponding ketone using the Noyori procedure., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

K(V)10.1 has recently become generally accepted as a promising cancer target, as it is ectopically expressed in the majority of solid tumors. Due to its cell-surface accessibility, K(V)10.1 has a strong potential for tumor treatment and diagnosis. Given that its mode of action is likely independent of conventional cancer pathways such as tyrosine kinases, K(V)10.1 opens a novel window for treating cancer. In this review we will give an overview of the current status of data linking K(V)10.1 to cancer, and propose techniques that could exploit K(V)10.1's properties for the management of cancer.

Labeling of RGD peptides with near-infrared fluorophores yields optical probes for noninvasive imaging of tumors overexpressing ανβ3 integrins. An important prerequisite for optimum detection sensitivity in vivo is strongly absorbing and highly emissive probes with a known fluorescence lifetime. The RGD-Cy5.5 optical probe was derived by coupling Cy5.5 to a cyclic arginine-glycine-aspartic acid-d-phenylalanine-lysine (RGDfK) peptide via an aminohexanoic acid spacer. Spectroscopic properties of the probe were studied in different matrices in comparison to Cy5.5. For in vivo imaging, human glioblastoma cells were subcutaneously implanted into nude mice, and in vivo fluorescence intensity and lifetime were measured. The fluorescence quantum yield and lifetime of Cy5.5 were found to be barely affected on RGD conjugation but dramatically changed in the presence of proteins. By time domain fluorescence imaging, we demonstrated specific binding of RGD-Cy5.5 to glioblastoma xenografts in nude mice. Discrimination of unspecific fluorescence by lifetime-gated analysis further enhanced the detection sensitivity of RGD-Cy5.5-derived signals. We characterized RGD-Cy5.5 as a strongly emissive and stable probe adequate for selective targeting of ανβ3 integrins. The specificity and thus the overall detection sensitivity in vivo were optimized with lifetime gating, based on the previous determination of the probes fluorescence lifetime under application-relevant conditions.

Molecular switches based on helical tetrasubstituted alkenes, substituted with either electron-withdrawing (CF(3), F, CN; 2a-c, 3a,c) or -donating substituents (Me, OMe; 2d,e), have been synthesized from acyclic precursors 4 and 5 in a domino carbopalladation/Stille reaction. This palladium-catalyzed process allowed the rapid assembly of two C-C bonds, two six-membered rings, and the tetrasubstituted double bond in a completely diastereoselective fashion. The electronic effects of the substituents on the overall switching process were investigated by alternating irradiation of two different wavelength regions. Although the substituents had only a small influence on the absorption maxima, drastic differences in the switching behavior were observed., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chemotherapy of malign tumors is usually associated with serious side effects as common anticancer drugs lack selectivity. An approach to deal with this problem is the antibody-directed enzyme prodrug therapy (ADEPT) and the prodrug monotherapy (PMT). Herein, the synthesis and biological evaluation of new glycosidic prodrugs suitable for both concepts are described. All prodrugs but one are stable in human serum and show QIC(50) values (IC(50) of prodrug/IC(50) of prodrug in the presence of the appropriate glycohydrolase) of up to 6500. This is the best value found so far for compounds interacting with DNA., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Breast cancer is the most common cause of cancer-related death worldwide, thus remaining a crucial health problem among women despite advances in conventional therapy. Therefore, new alternative strategies are needed for effective diagnosis and treatment. One approach is the use of oncolytic viruses for gene-directed enzyme prodrug therapy. Here, the lacZ-carrying vaccinia virus (VACV) strain GLV-1h68 was used in combination with a β-galactosidase-activatable prodrug derived from a seco-analog of the natural antibiotic duocarmycin SA. Tumor cell infection with the VACV strain GLV-1h68 led to production of β-galactosidase, essential for the conversion of the prodrug to the toxic compound. Furthermore, drug-dependent cell kill and induction of the intrinsic apoptosis pathway in tumor cells was also observed on combination therapy using the prodrug and the GLV-1h68 strain, despite the fact that VACV strains encode antiapoptotic proteins. Moreover, GI-101A breast cancer xenografts were effectively treated by the combination therapy. In conclusion, the combination of a β-galactosidase-activatable prodrug with a tumor-specific vaccinica virus strain encoding this enzyme, induced apoptosis in cultures of the human GI-101A breast cancer cells, in which a synergistic oncolytic effect was observed. Moreover, in vivo, additional prodrug treatment had beneficial effects on tumor regression in GLV-1h68-treated GI-101A-xenografted mice.

The treatment of cancer with common anti-proliferative agents generally suffers from an insufficient differentiation between normal and malignant cells which results in extensive side effects. To enhance the efficacy and reduce the normal tissue toxicity of anticancer drugs, numerous selective tumor therapies have emerged including the highly promising approaches ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT (Gene-Directed Enzyme Prodrug Therapy) and PMT (Prodrug Monotherapy). These allow a selective release of cytotoxic agents from non-toxic prodrugs at the tumor site either by targeted antibody-enzyme conjugates, enzyme encoding genes or by exploiting physiological and metabolic aberrations in cancerous tissue. Herein, recent developments in the design and biological evaluation of prodrugs for use in ADEPT, GDEPT and PMT are reviewed. As a highlight, a series of novel glycosidic prodrugs based on the natural antibiotics CC-1065 and the duocarmycins will be discussed which show a therapeutic window of up to one million. Notably, the corresponding drugs have tremendously high cytotoxicities with IC(50) values of down to 110 fM.

ortho-Haloarylcarbamates like 1-4 show a high rotational barrier about the N--aryl bond of up to 91.6 kJ mol(-1) as found for 1, which was determined by 2D exchange NMR spectroscopy (EXSY). It was further demonstrated that the height of the barrier not only depends on the substituents at the axis of chirality, but is also influenced by electronic effects.

The synthesis of the first spacer containing, duocarmycin analogue prodrug was realised, its biological properties evaluated and compared to its counterpart prodrug without a spacer unit. The synthesis comprises the manufacture of the new acetylated derivatives and of two double spacer systems, their activation and coupling to the pharmacophoric seco-drug (+)-. Unprecedented biological results were found as the new prodrug showed a fairly low QIC(50) value of 20, but on the other hand a high stability and very low DNA alkylation efficiency. These findings indicate a changed cytostatic mode of action induced by the self-immolative spacer moiety which was employed.

Datisca glomerata forms nitrogen-fixing root nodules in symbiosis with soil actinomycetes from the genus Frankia. Analysis of sugars in roots, nodules and leaves of D. glomerata revealed the presence of two novel compounds that were identified as alpha-L-rhamnopyranoside-(1 --> 6)-D-glucose (rutinose) and alpha-L-rhamnopyranoside-(1 --> 6)-1-O-beta-D-methylglucose (methylrutinose). Rutinose has been found previously as a/the glycoside part of several flavonoid glycosides, e.g. rutin, also of datiscin, the main flavonoid of Datisca cannabina, but had not been reported as free sugar. Time course analyses suggest that both rutinose and methylrutinose might play a role in transient carbon storage in sink organs and, to a lesser extent, in source leaves. Their concentrations show that they can accumulate in the vacuole. Rutinose, but not methylrutinose, was accepted as a substrate by the tonoplast disaccharide transporter SUT4 from Arabidopsis. In vivo (14)C-labeling and the study of uptake of exogenous sucrose and rutinose from the leaf apoplast showed that neither rutinose nor methylrutinose appreciably participate in phloem translocation of carbon from source to sink organs, despite rutinose being found in the apoplast at significant levels. A model for sugar metabolism in D. glomerata is presented.