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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 Suboptimal anti-Sars-Cov2 vaccine response has been demonstrated during immunosuppressive treatments. Liver Transplant Recipients (LTRs) and Inflammatory Bowel Disease (IBD) patients are different setting of populations who are both undergoing immunosuppressive treatments. In this work, we pooled and compared, retrospectively, these two populations to evaluate anti-SARS-CoV2 seroconversion after the second dose of vaccination. Different comorbidities and therapies outcomes have been explored as well. Methods The antibody titres standardized of the two cohorts have been analysed. Matched patients of both populations for comorbidities and therapies with application of propensity score have been investigated. Results 240 LTRs and 424 IBD patients were analysed. Most have received an mRNA based vaccine (BNT162b2 or mRNA-1273: 99.1%). The seroconversion rate of 84% for LTRs and 93% for IBD patients was recorded. To multivariate analysis, hypertension (OR 2.8618, 95% CI 1.0012 to 8.1802), the mycophenolate administration (OR 2.9733, 95% CI 1.1820 to 7.4794) and the steroid use (OR 5.4531, 95% CI 1.0706 to 27.7761) were significantly associated with reduced seroconversion in LTRs cohort; meanwhile, the older age (OR 1.0369, 95% CI 1.0076 to 1.0670) and the thiopurine consumption (OR 2.9484, 95% CI 1.0089 to 8.6166) with that in IBD population. After Propensity Score Matching application, the seroconversion rates, not statistically different, of 86% for LTRs and 92% for IBD patients were found. Hypertension (OR 2.73, 95%CI 1.1258 to 6.6138), diabetes (OR 3.16, 95% CI 1.1888 to 8.4217), age > 65y (OR 2.93, 95% CI 1.1712 to 7.3153) and the female sex (OR 2.54, 95% CI 1.0963 to 5.9104) were correlated with reduced seroconversion in both populations. Conclusion After Propensity Score Matching, the seroconversion rates of IBD and LTR patients were not statistically different. Hypertension, diabetes and age > 65y revealed a significant influence on seroconversion and the female showed a reduced seroconversion in comparison to male.

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)

The use of a triphenylarsonium vector for tumour cell-targeting leads to a dramatic increase in Gd3+ uptake in human glioblastoma multiforme cells by up to an order of magnitude over the isosteric triarylphosphonium analogue, with significant implications for ‘theranostic’ applications involving delivery of this important lanthanoid metal ion to tumour cells.

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.

The use of fluorescent markers and probes greatly enhances biological investigations but relies on the provision of an array of fluorophores with diverse properties. Herein we report a novel carborane-containing coumarin, 5, which is sufficiently lipophilic to localise in cellular lipid droplets. In non-polar solvents which show comparable polarities to those of a lipid environment, compound 5 exhibits a fluorescence quantum yield two orders of magnitude greater than found in aqueous solvents, adding a further degree of selectivity to lipid droplet imaging. Compound 5 can stain lipid droplets in ex vivo adipocytes as well as in cultured cells, and can be utilised in flow cytometry as well as confocal microscopy.

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.

Tryptophan to kynurenine metabolism is controlled by three distinct dioxygenase enzymes: tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2). Collectively, the activity of these enzymes contributes to tumour immune tolerance and immune dysregulation in a variety of disease pathologies, including cancer. Whereas IDO1 inhibitor drug design has been the focus of study for more than two decades (with novel compounds currently in Phase II clinical trials), only recently have the roles of TDO and IDO2 been elucidated in immunosuppression. Consequently, little comparative work on inhibitor cross-reactivity and selectivity has been performed. Here, we provide an overview of the current and future drug discovery landscape for targeting TDO, IDO1, and IDO2 (individually and collectively) for pharmacological intervention.

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)