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Bis-substituted cyclam derivatives have recently emerged as a promising new class of antibacterial agents, displaying excellent activity against drug-resistant Mycobacterium tuberculosis (Mtb). Carborane pendants enhance this activity.

Background With recent advances in novel approaches to cancer therapy and imaging, the application of theranostic techniques in personalised medicine has emerged as a very promising avenue of research inquiry in recent years. Interest has been directed towards the theranostic potential of Rare Earth radiometals due to their closely related chemical properties which allow for their facile and interchangeable incorporation into identical bifunctional chelators or targeting biomolecules for use in a diverse range of cancer imaging and therapeutic applications without additional modification, i.e. a “one-size-fits-all” approach. This review will focus on recent progress and innovations in the area of Rare Earth radionuclides for theranostic applications by providing a detailed snapshot of their current state of production by means of nuclear reactions, subsequent promising theranostic capabilities in the clinic, as well as a discussion of factors that have impacted upon their progress through the theranostic drug development pipeline. Main body In light of this interest, a great deal of research has also been focussed towards certain under-utilised Rare Earth radionuclides with diverse and favourable decay characteristics which span the broad spectrum of most cancer imaging and therapeutic applications, with potential nuclides suitable for α-therapy (149Tb), β−-therapy (47Sc, 161Tb, 166Ho, 153Sm, 169Er, 149Pm, 143Pr, 170Tm), Auger electron (AE) therapy (161Tb, 135La, 165Er), positron emission tomography (43Sc, 44Sc, 149Tb, 152Tb, 132La, 133La), and single photon emission computed tomography (47Sc, 155Tb, 152Tb, 161Tb, 166Ho, 153Sm, 149Pm, 170Tm). For a number of the aforementioned radionuclides, their progression from ‘bench to bedside’ has been hamstrung by lack of availability due to production and purification methods requiring further optimisation. Conclusions In order to exploit the potential of these radionuclides, reliable and economical production and purification methods that provide the desired radionuclides in high yield and purity are required. With more reactors around the world being decommissioned in future, solutions to radionuclide production issues will likely be found in a greater focus on linear accelerator and cyclotron infrastructure and production methods, as well as mass separation methods. Recent progress towards the optimisation of these and other radionuclide production and purification methods has increased the feasibility of utilising Rare Earth radiometals in both preclinical and clinical settings, thereby placing them at the forefront of radiometals research for cancer theranostics.

The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.

Histone deacetylase enzymes (HDACs) are responsible for the global silencing of tumour-suppressor genes. Treatment with a histone deacetylase inhibitor (HDACi) can reverse this process and restore normal cell function. Herein, we report a small series of boron-based (boronic acid, boronate ester and closo-1,2-carborane) HDAC2 inhibitors with IC50 values in the nanomolar range. The boronate ester 4 b was the most potent compound assessed in this study (IC50 =40.6±1.5 nM), followed closely by the 1,2-closo-carborane (IC50 =42.9±1.5 nM). Compound 4 b exceeds the potency of the related gold-standard HDAC pan-inhibitor vorinostat (1) toward this particular HDAC isoform.

Episode of haemoptysis in a 25–year–old woman with the following medical history: surgical closure of Botallo‘s duct at the age of 5 months, coeliac disease, growth retardation, polycystic ovary, visus alterations. In the emergency room CT angiography of the chest showed the presence of subpleural parenchymal consolidation in the right lower lobe, with associated ground–glass opacities, cardiomegaly, severe pulmonary artery dilatation and hepatomegaly with intrathoracic involvement by a hernia of Morgagni on the right side. A porto–systemic shunt with an intrahepatic course was also noted in the duct at the VIII segment with an autonomic outlet in the right atrium. The patient was transferred to the Internal Medicine ward. Objective examination revealed an elf facies with hypertelorism, short stature, bradypsychism. On interview she reported dyspnoea on light exertion and frequent lipohymic episodes. Haematochemical examinations showed increased of bilirubinemia mainly indirect, Transaminases and of NTproBNP and normal ammonium levels. Blood gas analysis showed a tendency to respiratory alkalosis with oxyaemia at lower limits. Because of the suspicion of a syndromic picture, a genetic examination was performed. Cardiological evaluation showed a high ultrasound probability of pulmonary hypertension (PH). Transferred to cardiology, catheterisation confirmed pulmonary arterial hypertension (mPAP 64mmHg) precapillary (wedge 4mmHg) with high PVR (11 Wood Units) not responsive to nitric oxide. In addition, there was a superior vena cava protruding into the coronary sinus and an extrahepatic shunt with an isolated outlet in the RA without gradient. The hepatobiliary surgery consultation concluded for Abernethy syndrome, which is a rare congenital syndrome characterised by an extrahepatic portosystemic shunt in which the blood from the splanchnic and lienal circulation bypasses the portal vein and the liver, draining into the systemic circulation via an abnormal conduit. PH is a rare complication of this syndrome, maintained by hyperafflux, vasoactive mediators and the formation of microthrombi and intimal fibrosis in the pulmonary circulation. An HR–CT excluded venulo–capillary plexiform disease. Macitentan 10 mg/day was introduced, then continued at home for the benefit shown and follow–up at the Pulmonary Work Group was initiated. This PH, due to its association with an extremely rare pathology, required the collaboration of a diverse group of specialists.

The synthesis and characterisation of five new boron-based coumarin fluorophores are reported, with key structural variations involving the linker at the C3-position (hydrazone or imine) of the 7-(diethylamino)-coumarin (7DEAC) core and the terminal boron moiety (i.e. boronic acid or closo-1,2-carborane). All the coumarin derivatives were found to display significant bathochromic shifts relative to the parent 7DEAC, with conjugate ICCb displaying the greatest overall shift. Confocal microscopy studies with A549 lung cancer cells showed clear differences in the observed intra-cellular distributions of the fluorophores. The polar boronic acid species (HCoBA, HCmBA and HCpBA) were found to localise in the endoplasmic reticulum. In contrast, the lipophilic closo-1,2-carborane derivatives (HCCb and ICCb) were found to localise within lipid droplets (LDs), showcasing the future potential for these probes to be utilised as stains for LD observations by means of confocal microscopy.

The first examples of adenine binding by isomeric organoplatinum(II) complexes bearing H-bonding nicotinic and isonicotinic acid ligands are reported. Notably, a subtle switching of the H-bonding functionality from the 3- to 4-position of the pyridyl ring leads to a significant change in both the strength of association and the site of adenine binding. Australian Research Council (ARC)

According to the World Health Organization (WHO), there were 18.1 million new cancer cases and 9.6 million cancer deaths reported worldwide in 2018. These numbers are expected to rise over the next decade, and the development of new and effective cancer treatments and diagnostic tools is urgently required, particularly for aggressive and intractable malignant cancers such as those of the brain. An exciting field of cancer research involves combining therapeutic and diagnostic tools into a single 'theranostic' platform. The role of theranostics in the personalized management of oncology patients is increasing, as is the demand for new types of theranostic agents. Some of the most promising cancer theranostics exploit the lanthanoid metal gadolinium, an element possessing favourable therapeutic and imaging properties.

The synthesis of a new series of Gd(III)-arylphosphonium complexes is described and the solution stability of selected compounds is reported. Their lipophilicity and uptake in human glial (SVG p12) and human glioblastoma multiforme (T98G) cell lines are presented. The in vitro cytotoxicity of all complexes was determined to be low at therapeutically-relevant concentrations. Selected Gd(III) complexes are potential candidates for further investigation as theranostic agents.

Cubane is a highly strained saturated hydrocarbon system that has historically been of interest in theoretical organic chemistry. More recently it has become a molecule of interest for biological applications due to its inherent stability and limited toxicity. Of greater significance is the ability to potentially functionalize cubane at each of its carbon atoms, providing complex biologically active molecules with unique spatial arrangements for probing active sites. These characteristics have led to an increased use of cubane in pharmaceutically relevant molecules. In this Perspective we describe synthetic methodology for accessing a range of functionalized cubanes and their applications in pharmaceuticals. We also provide some perspectives on challenges and future directions in the advancement of this field.

Sintetico quadro delle ricerche storico-archeologiche condotte dall'Università del Salento nel complesso santuariale del Monte San Nicola a Pietravairano (CE)

Delocalized lipophilic cations such as tri- and tetra-arylphosphonium are able to diffuse across the mitochondrial membrane, which allows them to selectively accumulate in cells with a high transmembrane potential (ΔΨm). The mitochondrial membrane potential of cancer cells and cardiomyocytes has been reported to be significantly higher than that of normal epithelial cells. This feature can be exploited for the selective accumulation of phosphonium derivatives for the purposes of molecular imaging using radionuclides. Four structurally related Ga(III)-phosphonium salts were synthesized and fully characterized and found to be modest in toxicity toward T98G human glioblastoma cells (IC50 > 4 mM). High-activity (100 MBq) analogs containing Ga-67 were also synthesized and their stabilities in phosphate-buffered saline and human serum were determined.

Usnic acid is a secondary metabolite abundantly found in lichens, for which promising cytotoxic and antitumor potential has been shown. However, knowledge concerning activities of its derivatives is limited. Herein, a series of usnic acid derivatives were synthesized and their antiproliferative potency against cancer cells of different origin was assessed. Some of the synthesized compounds were more active than usnic acid. Compounds 2a and 2b inhibited survival of all tested cancer cell lines in a dose- and time-dependent manner. Their IC50 values after 48 h of treatment were ca. 3 μM for MCF-7 and PC-3 cells and 1 μM for HeLa cells, while 3a and 3b revealed antiproliferative activity only against HeLa cells. All active usnic acid derivatives induced G0/G1 arrest and a drop in the fraction of HeLa cells in the S and G2/M phases. Compounds 2a and 2b decreased the clonogenic potential of the cancer cells evaluated and induced cell cycle arrest at the G0/G1 phase and apoptosis in MCF-7 cells. Moreover, they induced massive cytoplasmic vacuolization, which was associated with elevated dynein-dependent endocytosis, a process that has not been reported for usnic acid and indicates a novel mechanism of action of its synthetic derivatives. This work also shows that naturally occurring usnic acids are promising lead compounds for the synthesis of derivatives with more favorable properties against cancer cells.

2019 is the International Year of the Periodic Table of Chemical Elements (IYPT 2019), as declared by the United Nations General Assembly. This invited paper on boron is one in a series of essays about the chemical elements.

This report summarizes the clinical features and the indications for treating HCV infection in immunocompromised and transplanted patients in the Direct Acting Antiviral drugs era.

Novel boron‐rich, carboranyl–indole carboxamide ligands were prepared and found to effectively target the 18 kDa translocator protein (TSPO), an upregulated mitochondrial membrane‐bound protein which has been observed in variety of tumor cell lines and its expression appears to be proportional to the degree of tumorigenicity, emphasizing a key role in cancer cell proliferation. Both boronated compounds displayed remarkably high affinities for the TSPO. In addition, the in vitro uptake of these compounds into T98G human glioma cells was found to be 25‐ to 100‐fold greater than that of clinical boron neutron capture therapy (BNCT) agents. Australian Research Council (ARC), Prostate Cancer Foundation of Australia, National Breast Cancer Foundation

The aim of this trial was to evaluate ghrelin response to milk administration in 20 days old buffalo calves. The trial was carried out on 5 female buffalo calves with a mean age of 21.2±2.8 days. Five blood samples were collected from each animal into EDTA tubes, starting at 07.00 until 15.00, at 2-h intervals. At 09.00, after the second blood sample, replaced milk was administered to the calves. Blood samples were immediately placed at 4°C until processing, which was performed on the same day. We used real-time reverse transcription PCR system to detect the expression of ghrelin mRNA levels in blood of buffalo calves. Two calves showed a low ghrelin concentration at the start of the trial (Group A = low ghrelin concentration) and three calves a high ghrelin concentration (Group B = high ghrelin concentration). Ghrelin expression was significantly higher either two hours (P

The synthesis of a series of bifunctional Gd(III) complexes 1–3 covalently bound to arylphosphonium cations possessing a varying degree of delocalisation at the phosphonium centre is presented. The influence of the degree of delocalisation was investigated with regards to in vitro cytotoxicity, cellular uptake of Gd, tumor-cell selectivity and intracellular localisation of Gd within human glioblastoma (T98G) and human glial (SVG p12) cells. Cellular uptake and selectivity studies for the Gd(III) complexes indicate that a reduced delocalisation at the phosphonium centre can lead to an enhanced Gd uptake into SVG p12 cells which results in a decrease in the overall tumor cell selectivity. Synchrotron X-ray fluorescence (microbeam XRF) imaging has demonstrated for the first time that uniform uptake of Gd(III) complex 2 within a population of T98G cells increased as a function of increasing Gd incubation times. The Gd maps show dispersed spots of high intensity which are consistent with mitochondrial uptake. Australian Research Council (ARC DP120100958 and ARC DP140100176)

An efficient synthesis of an 18F-labelled phosphonium salt containing closo-carborane is described. The preparation of this salt was attempted using both single-step and two-step protocols, with greater success found for the latter. An X-ray structure for the unlabelled 19F salt is also presented. Australian Research Council (ARC)

A structure–activity relationship study of a library of novel bifunctional GdIII complexes covalently linked to arylphosphonium cations is reported. Such complexes have been designed for potential application in binary cancer therapies such as neutron capture therapy and photon activation therapy. A positive correlation was found between lipophilicity and cytotoxicity of the complexes. Mitochondria uptake was determined by means of inductively coupled plasma mass spectrometry (ICP‐MS), and Gd uptake was determined by means of quantification using synchrotron X‐ray fluorescence (XRF) imaging. A negative correlation between lipophilicity and tumour selectivity of the GdIII complexes was demonstrated. This study highlights the delicate balance required to minimise in vitro cytotoxicity and optimise in vitro tumour selectivity and mitochondrial localisation for this new class of mitochondrially‐targeted binary therapy agents. We also report the highest in vitro tumour selectivity for any Gd agent reported to date, with a T/N (tumour/normal cell) ratio of up to 23.5±6.6. Australian Research Council (ARC)

We report the first example of an ionic graphene salt containing boron. An anionic charge is introduced to the graphene surface by means of 7,8-nido-[C2B9H11]− carborane clusters covalently and electronically bound to the graphene lattice, and this new material was isolated as its Cs+ salt. The University of Sydney, Australian Research Council (ARC), ARC LIEF Scheme (UNSW, ARC LE0989541)

A chiral, isomeric series of novel boron-rich Pt(II) metallointercalators ([PtL2(phen)](NO3)2: L = (x)-(1,y-closo-carboran-1-yl)pyrid-z-ylmethanol: x = R, S; y = 7, 12; z = 3, 4) wre prepared and fully characterized. By means of variable-temperature NMR spectroscopy, different combinations of Δ-head-to-tail, head-to-head, and Λ-head-to-tail rotamers were identified, and the free energies of activation for Pt-N bond rotation were determined for the pyrid-4-yl complexes with ΔG(‡)307 = 16.1 ± 0.3 kcal mol(-1) and ΔG(‡)325 = 16.2 ± 0.5 kcal mol(-1) for the 1,7-carboranyl derivative and ΔG(‡)307 = 16.4 ± 0.5 kcal mol(-1) and ΔG(‡)325 = 16.2 ± 0.5 kcal mol(-1) for the 1,12-carboranyl derivative. The corresponding 2:1 host-guest β-cyclodextrin (β-CD) adducts ([PtL2(phen)·2β-CD](NO3)2) were also prepared and fully characterized by high resolution electrospray ionization mass spectrometry and 2D-(1)H{(11)B} nuclear Overhauser enhancement spectroscopy and rotating-frame Overhauser effect spectroscopy NMR experiments. The interaction of the novel supramolecular adducts with calf thymus DNA was investigated by means of linear dichroism, ultraviolet-visible spectroscopy, thermal denaturation, and isothermal titration calorimetry experiments which revealed a bimodal binding regime with DNA intercalation favored at low [drug]/[DNA] ratios, while at higher drug loading, surface aggregation was observed. Furthermore, the data were also consistent with some degree of dissociation of the β-CD host-guest adducts upon DNA binding. When we used a single binding-site model, interpreted as a weighted average of all of the possible equilibrium interactions, the compounds showed high affinity for ct-DNA with K(assoc) ranging from (1.3 ± 0.1) × 10(5) M(-1) to (5.7 ± 0.4) × 10(5) M(-1). In general, the overall DNA-binding behavior was enthalpically driven with a minor or unfavorable entropic component, which is consistent with the thermodynamics of an intercalation-dominated process. A higher degree of DNA intercalation was observed for the R-isomer in the pyrid-3-yl compounds, and the opposite trend was observed in the case of pyrid-4-yl derivatives.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P

The first example of synchrotron X-ray fluorescence imaging of cultured mammalian cells in cyclic peptide research is reported. The study reports the first quantitative analysis of the incorporation of a bromine-labelled cyclic RGD peptide and its effects on the biodistribution of endogenous elements (for example, K and Cl) within individual tumor cells. Australian Research Council (ARC), Sydney Cancer Research Fund, Australian Synchrotron Research Program, Commonwealth of Australia Major National Research Facilities Program, US Department of Energy Office of Science

The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups. Guided by this pharmacophore, S1R ligands containing piperazines, piperazinones, and ethylenediamines have been developed. In the current work, we systematically deconstructed the piperazine core of a prototypic piperazine S1R ligand (vide infra) developed in our laboratories. Although we did not improve the affinity at the S1R compared to the lead, we identified several features important for affinity and selectivity. These included at least one basic nitrogen atom, conformational flexibility and, for S1R, a secondary or tertiary amine group proximal to the anisole. Furthermore, S2R selectivity can be tailored with functional group modifications of the N-atom proximal to the anisole.

Aim of this study was to verify the relation among the mediators and indicators of nutritional status like insulin, glucagon, urea, cholesterol, triglycerides and total proteins in growing buffalo heifers, fed diets with different energy density. 12 Murrah heifers were randomly allocated into two dietary treatments (High, Group H; Low, Group L) that differed in energetic levels (Group H: 5.8 UFL/d; Group L: 3.6 UFL/d). Every 30 days, for a total of five times, blood samples were collected at 08.00 h, before feeding, from the jugular vein in vacutainer tubes and analysed to determine metabolic profile. Data on haematic constants were analysed by ANOVA for repeated measures with treatment as the main factor. Low energy availability and low NSC reduced the glucose and insulin and increased glucagone and urea blood levels. The increase of NSC in the diet of group H during the experiment may caused a reduction of the fibre digestibility after the period of adaptation of the rumen microflora and, as a paradox effect, suffered for an energetic lack with a subsequent activation of lipolysis and mobilization of their body reserves. Liver and muscular synthesis increase in group with a high energy availability.

The synthesis of six new compounds incorporating either a pyrazino[2,3-b]indolizine or indolizino[2,3-b]quinoxaline core are reported in good yield (58–87%). The intermediates for the key cyclization reaction for one set of compounds (5a–c), with a sterically demanding 3,5-dimethylpyrazole group in the 5-position of the core, were found to be mono-substituted. These intermediates could be isolated and cyclized by heating under acid-catalyzed conditions. To further demonstrate the versatility of the chemistry, compounds 6a–c were synthesized in 58–68% yields. Compounds 5a–c are non-planar in solution and the solid-state, while 6a–c have close to planar conformations, pointing to weak hydrogen bonds between the acidic C–Hs and the adjacent azine nitrogen atoms. The cytotoxicity of the six newly synthesized and three previously prepared compounds was assessed against a human glioblastoma multiforme cell line.

A series of cationic, ditopic N-donor ligands based on 4,4'-bipyridine (4,4'-bipy), 3-aminopyrazine (apyz) and 2-aminopyrimidine (apym), each incorporating two positively-charged N-heterocycles linked by a conformationally-flexible spacer unit, have been synthesised and treated with palladium(II) or platinum(II) precursors [M(2,2'-bipy)(NO(3))(2)] (M = Pd(II) or Pt(II)) to form highly cationic metallocyclic species. Treatment of 1,6-bis(4,4'-bipyridinium)hexane nitrate with [M(2,2'-bipy)(NO(3))(2)] in aqueous solution, followed by the addition of KPF(6), resulted in the formation of the [2+2] species [M(2)(2,2'-bipy)(2){4,4'-bipy(CH(2))(6)4,4'-bipy}(2)](PF(6))(8). Treatment of [Pd(PhCN)(2)Cl(2)] with 1,3-bis(4,4'-bipyridinium)propane hexafluorophosphate in MeCN afforded [Pd(2)Cl(4){4,4'-bipy(CH(2))(3)4,4'-bipy}(2)](PF(6))(4). When the cationic apyz or apym ligands were used in aqueous solution, the analogous metallomacrocycles did not form. Instead, deprotonation of the exocyclic amino group occurred upon coordination of the ligand to afford a tetranuclear [4+2] species in the case of platinum(II), with Pt(II)...Pt(II) bonding supported by strong UV-vis absorption at lambda = 428 nm which was assigned to a metal-metal-to-ligand charge transfer (MMLCT) band. Thus, treatment of 1,6-bis(3-aminopyrazinium)hexane nitrate with [Pt(2,2'-bipy)(NO(3))(2)], followed by the addition of KPF(6), led to the formation of the red species [Pt(4)(2,2'-bipy)(4){apyz(CH(2))(6)apyz-2H}(2)](PF(6))(8). No related products could be identified with palladium(II), consistent with the low propensity for this metal ion to form strong Pd(II)...Pd(II) bonding interactions.

The preparation and characterization of cationic, dinuclear complexes of the type trans-[Pt(PPh3)2(σ-C6H4NHMe)-µ-L-Pt(PPh3)2(σ-C6H4NHMe)](OTf)2 (L = 4,4′-bipyridine, 4,7-phenanthroline, 4,4′-dipyrazolylmethane, and 1,1′-diphenyl-4,4′-dipyrazolylmethane; OTf = trifluoromethanesulfonate (triflate)) containing two C3-N-methylbenzamide ligands are described. The key structural feature of the cationic complexes is the presence of two convergent amide groups that may allow for charge-assisted, H-bonding interactions in solution with suitable heteroaromatic guest molecules such as nucleobases.Key words: organoplatinum(II) complex, organometallic host, dinuclear complex, N-methylbenzamide.

We show that changing the number and position of nitrogen atoms in the heteroatomic core of a pyrazolopyrimidine acetamide is sufficient to induce complex binding to wild type human TSPO. Only compounds with this complex binding profile lacked intrinsic effect on glioblastoma proliferation but positively modulated the antiproliferative effects of a synthetic TSPO ligand. To the best of our knowledge this is the first demonstration of allosteric-like interaction at the wild type human TSPO.

Illustrazione dei risultati della campagna di scavo condotta nel 2012 presso il santuario del Monte San Nicola a Pietravairano (CE)

The mononuclear σ-aryl complexes of the type trans-[Pt(σ-C6H4R)(4,7-phen)(PPh3)2]OTf (R=4-CO2SitBuPh2, 4-CONHMe, 3-CO2SitBuPh2, 3-CONHMe; OTf=trifluoromethanesulfonate) containing a monodentate 4,7-phenanthroline (4,7-phen) ligand were prepared by an oxidative addition reaction of an aryl iodide with Pt(PPh3)4 to yield the key iodoplatinum(II) precursors trans-[PtI(σ-C6H4R)(PPh3)2], followed by halogen metathesis with one equivalent of 4,7-phen. The reaction of trans-[Pt(σ-C6H4R)(4,7-phen)(PPh3)2]OTf with labile complexes of the type trans-[Pt(OTf)L2(σ-C6H4R ′ )] (L=PEt3, R ′ =H; L=PPh3, R ′ =4-CO2SitBuPh2, 3-CO2SitBuPh2, 3-CONHMe) afforded the asymmetric dinuclear complexes of the type trans-[Pt(σ-C6H4R)L2(μ-4,7-phen)Pt(σ-C6H4R ′ )L ′ 2](OTf) 2 (L=PPh3, R=4-CO2SitBuPh2, L ′ =PEt3, R ′ =H; L=L ′ =PPh3, R=4-CONHMe, R ′ =4-CO2SitBuPh2; R=4-CO2SitBuPh2, R ′ =3-CONHMe; R=3-CONHMe, R ′ =3-CO2SitBuPh2) in which the 4,7-phen acts as a bridging bidentate ligand. The novel dinuclear species undergo an unusual redistribution reaction that is essentially thermoneutral at 298 K. The exchange process involves facile cleavage of a Pt–N bond and the rapid exchange of trans-[PtL2(σ-aryl)] units in the equilibrium mixture.

DYRK1A is a novel target for epidermal growth factor receptor (EGFR)-dependent glioblastoma and it represents a promising strategy for cancer therapy. DYRK1A inhibition has been found to promote EGFR degradation in glioblastoma cells by triggering endocytosis and lysosomal degradation, thus reducing the self-renewal ability of tumorigenic cells. Using a deconstruction approach of a DYRK1A lead molecule DANDY (1a), a set of novel ring-opened compounds was prepared. Despite showing no activity towards DYRK1A, a reduction in the viability of glioblastoma cells was observed with some of the compounds. This suggests other mechanistic pathways are leading to the apoptosis of glioblastoma cells.

Two C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes, 1-(BMes2)-2-R-1,2-C2B10H10 (1, R = H, 2, R = Ph), were synthesised by lithiation of 1,2-dicarba-closo-dodecaborane and 1-phenyl-1,2-dicarba-closo-dodecaborane, respectively, with n-butyllithium and subsequent reaction with fluorodimesitylborane. These novel compounds were structurally characterised by X-ray crystallography. Compounds 1 and 2 are hydrolysed on prolonged exposure to air to give mesitylene and boronic acids 1-(B(OH)2)-2-R-1,2-C2B10H10 (3, R = H, 4, R = Ph respectively). Addition of fluoride anions to 1 and 2 resulted in boryl-carborane bond cleavage to give dimesitylborinic acid HOBMes2. UV absorption bands at 318–333 nm were observed for 1 and 2 corresponding to local π–π*-transitions within the dimesitylboryl groups while visible emissions at 541–664 nm with Stokes shifts of 11[thin space (1/6-em)]920–16[thin space (1/6-em)]170 cm−1 were attributed to intramolecular charge transfer transitions between the mesityl and cluster groups. Compound 2 was shown by cyclic voltammetry to form a stable dianion on reduction. NMR spectra for the dianion [2]2− were recorded from solutions generated by reductions of 2 with alkali metals and compared with NMR spectra from reductions of 1,2-diphenyl-ortho-carborane 5. On the basis of observed and computed 11B NMR shifts, these nido-dianions contain bowl-shaped cluster geometries. The carborane is viewed as the electron-acceptor and the mesityl group is the electron-donor in C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes. Deutsche Forschungsgemeinschaft (DFG), Engineering and Physical Sciences Research Council (EPSRC), EPSRC Leadership Fellowship, ARC Future Fellowship (FT120100073)

Sofosbuvir (SOF) treatment ± ribavirin (RBV) prior to LT has the potential to change the HCV recurrence after Liver Transplantation (LT). This approach has been reported to avoid graft reinfection in compensated patients with hepatocellular carcinoma (HCC), but only among those who reached and maintained undetectable HCV-RNA (TND) before LT. Since the time to obtain this result in decompensated cirrhotics is unknown, we sought to investigate the early HCV-RNA decay in this setting. Sixteen decompensated patients (M/F 12/4, median age 55.3, CPT score>=B7), infected by HCV genotype 1a, 1b, 3 and 4 (2-8- 4-2), 4 of whom with HCC, were treated with SOF 400mg/day and RBV (200-1000 mg/day), except 2 who received SOF alone, for a median(IQR) of 12(11-16) weeks awaiting LT. HCV-RNA levels were measured weekly and safety and clinical parameters were analyzed. No serious adverse events were reported. The median(IQR) RBV dose was 600(400-800). Despite 11/16 patients had low baseline viremia (

The conjugated aromatic system of graphene was used to trap the reactive, boron-rich 1,2-carborane cluster. Functionalization of the graphene surface was confirmed by solid-state MAS 11B NMR spectroscopy and quantified by X-ray photoelectron spectroscopy. This work represents the first confirmed example of direct functionalization of a graphene lattice with carboranes. University of Sydney, Australian Research Council (ARC)

Indoleamine-2,3-dioxygenase-1 (IDO1) is a critical immunoregulatory enzyme responsible for the metabolism of tryptophan during inflammation and disease. Based upon a pyranonaphthoquinone framework, the first examples of indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing a carborane cage are reported. The novel closo-1,2-carboranyl-N-pyranonaphthoquinone derivatives display low μM binding affinity for the human recombinant enzyme, with IC50 values ranging from 0.78 to 1.77 μM. Australian Research Council (ARC), NBCF

Relative to other polycyclic frameworks (1–3), a carborane cage (4 and Cs·5) exerts a significant biological effect as an inhibitor of the purinergic P2X7 receptor (P2X7R) which allows one to target depression in vivo and thus demonstrate, for the first time, that a carborane has the capacity to modify CNS activity.

The preparation and characterisation of a series of novel, dinuclear organoplatinum(II) complexes of methyldiphenylphosphine, trans-[Pt(PMePh2)2(C5H4N(CO2H))-μ-aryl-Pt(PMePh2)2(C5H4N(CO2H))](OTf)2 (aryl=phenyl, 4,4′-biphenyl, 4,4′′-p-terphenyl, or 4,4′-benzophenone; OTf=triflate), in which nicotinic acid acts a nitrogen-donor ligand are described. The key structural feature of each complex is the presence of a carboxylic acid group at each end of the molecule. This allows for their association via intermolecular hydrogen-bonds in low polarity solvents. The complexes are potentially useful tectons (building blocks) for the construction of metal-containing supramolecular assemblies.