Search

Intermolecular carbophosphination reaction of alkynes or alkenes with unreactive C-P bonds remains an elusive challenge. Herein, we used a Ni-Al bimetallic catalyst to realize an intermolecular carbophosphination reaction of alkynes with 5-membered phosphole oxides, providing a series of 7-membered phosphepines in up to 94 % yield., (© 2023 Wiley-VCH GmbH.)

A novel persulfate-mediated oxidative glycosylation system using p -methoxyphenyl (PMP) glycosides as bench-stable glycosyl donors is developed. This study shows that both K 2 S 2 O 8 as an oxidant and Hf(OTf) 4 as a Lewis acid catalyst play important roles in the oxidative activation of the PMP group into a potential leaving group. This convenient glycosylation protocol proceeds under mild conditions and delivers a wide range of biologically and synthetically valuable glycoconjugates, including glycosyl fluorides.

Background: Access to cancer care is an issue in low and low middle-income countries. The problem is worse with respect to access to new therapies like checkpoint inhibitors. Hence, we decided to audit our practice in the head and neck and thoracic medical oncology unit from 2015 to 2019 to study the accessibility of checkpoint inhibitors and factors influencing it., Methods: All patients who were registered in the head and neck and thoracic medical oncology unit between 2015 and 2019 were included in the study. Patients who received immunotherapy were identified from the prospective database of immunotherapy maintained by the department. We made a list of patients who were eligible for immunotherapy per year and identified how many of them received recommended immunotherapy. The indication for eligibility of immunotherapy was based on published pivotal data and it was applicable from the date of publication of the study online. Descriptive statistics were performed. For nominal and ordinal variable percentage with 95% confidence intervals (95% CI) was provided. Factors impacting the accessibility of immunotherapy were identified., Findings: A total of 15,674 patients were identified who required immunotherapy; out of them only 444 (2.83%, 95% CI: 2.58-3.1) received it. Among head and neck cancer patients, 4.5% (156 out of 3,435) received immunotherapy versus 2.35% (288 out of 12,239) among thoracic cancer patients ( p < 0.001). Among the general category (low socioeconomic), 0.29% (28 out of 9,405 ) versus 6.6% (416 out of 6,269) among the private category (high socioeconomic) received immunotherapy ( p < 0.001). While 3.7% (361 out of 9,737) among males versus 1.39% (83 out of 5,937) females received immunotherapy ( p < 0.001). There was also a temporal trend seen in the accessibility of immunotherapy ( p < 0.001)., Conclusion: The accessibility of immunotherapy is below 3% in India. Patients with head and neck cancers, those registered as private category and male patients had higher access to this therapy. There was also a temporal trend observed suggesting increased accessibility over the years., Competing Interests: The authors certify that they have no affiliations with or involvement in any organisation or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© the authors; licensee ecancermedicalscience.)

Background: Recurrent glioblastoma (GBM) has dismal outcomes and limited treatment options. Mebendazole (MBZ) has activity in glioma both in-vivo and in-vitro , and is well tolerated in combination with lomustine (CCNU) and temozolomide (TMZ). In this study, we sought to determine whether the addition of MBZ to CCNU or TMZ would improve overall survival (OS) in recurrent GBM., Methods: In this phase II randomized open-label trial, adult patients with ECOG PS 0-3, with recurrent GBM who were not eligible for re-radiation, were randomized 1:1 to the CCNU-MBZ and TMZ-MBZ arms. CCNU was administered at 110 mg/m 2 every 6 weeks with MBZ 800 mg thrice daily and TMZ was administered at 200 mg/m 2 once daily on days 1-5 of a 28 days cycle with MBZ 1600 mg thrice daily. The primary endpoint was OS at 9 months. A 9-month OS of 55% or more in any arm was hypothesized to warrant further evaluation and a value below 35% was too low to warrant further investigation. OS was analyzed using intention to treat (ITT) and per-protocol (PP) analyses. Per-protocol analysis was used for safety analysis. Clinical Trials Registry-India number, CTRI/2018/01/011542., Findings: Participants were recruited from 14 th March 2019 to 18 th June 2021, 44 patients were randomised on each arm. At 17.4 months, 68 events for OS analysis had occurred, 33 in the TMZ-MBZ and 35 in the CCNU-MBZ arm. The 9-month OS was 36.6% (95% CI 22.3-51.0) and 45% (95% CI 29.6-59.2) in the TMZ-MBZ and CCNU-MBZ arms respectively, in the ITT population. ECOG PS was the only independent prognostic factor impacting OS (HR-0.48, 95% CI 0.27-0.85; P  = 0.012). Grade 3-5 adverse events were seen in 8 (18.6%; n  = 43) and 4 (9.5%; n  = 42) patients in the TMZ-MBZ and CCNU-MBZ arms respectively. There were no treatment related deaths., Interpretation: The addition of MBZ to TMZ or CCNU failed to achieve the pre-set benchmark of 55% 9-month OS. This was probably due to 28.6% of patients having poor PS of 2-3., Funding: Brain Tumor Foundation (BTF) of India, Indian Cooperative Oncology Network (ICON), and India Cancer Research Consortium (ICRC) under ICMR (Indian Council of Medical Research)., Competing Interests: VP reports research grants from Brain Tumor Foundation (BTF) of India, grants from Indian Cooperative Oncology Network (ICON), grants from India Cancer Research Consortium (ICRC) under ICMR (Indian Council of Medical Research), during the conduct of the study; and research grants from Janssen & Janssen, Astra Zeneca, Intas Pharmaceuticals, Natco Pharma, Cadila Healthcare, Eisai, and Novartis outside the submitted work. NM reports a research grant from Astra Zeneca outside the submitted work. All grants were paid to the institution. All other authors report no conflicts of interest., (© 2022 The Authors.)

A new synthetic route for the total synthesis of dendrodolide-L has been developed from known chiral epoxides. The key reactions involved in this synthesis are regioselective ring-opening of epoxide, Yamaguchi esterification and ring-closing metathesis reactions (RCM) to result the target compound.

Ebolavirus (EBOV) is the etiology of Ebola hemorrhagic fever (EHF). A major EHF outbreak in 2014-2015 in West Africa claimed >11,000 lives. A licensed vaccine is not available for EHF, although several vaccines have undergone clinical trials. We developed a human adenovirus (Ad) serotype 5-based candidate EHF vaccine based on controlled expression of the EBOV (Makona strain) glycoprotein (GP) as the immunogen. Two clones, AdGP72 and AdGP75, and a control Ad515 vector, were generated and tested for protein expression in vitro and immunogenicity in mice. Eight groups of mice were immunized with three doses of buffer, Ad515, AdGP72, and AdGP75, by two different dose regimens. Three different antigens (AdGP75-infected Vero E6 cell extract and two baculovirus expressed EBOV GP antigens, namely, GP alone or GP with EBOV VP40) were used to evaluate the immune response. Expression studies indicated that full-length GP was cleaved into its component subunits when expressed in mammalian cells through the Ad vectors. Moreover, in coimmunoprecipitation studies, EBOV GP was found to be associated with VP40 when expressed in baculoviruses. The candidate vaccines were immunogenic in mice, as evaluated by enzyme-linked immunosorbent assay using mammalian- or baculovirus-derived antigens. Further characterization and development of the candidate vaccines are warranted.

Addition of arylboronic acids to directing group tethered acetylenes in a regio and stereoselective manner using an inexpensive catalytic system is achieved for the first time to access highly sought after allyl/homoallyl alcohol/amine units. The apparent vinylnickel intermediate was successfully trapped by the Michael electrophiles to get defined tri- and tetra-substituted olefins. An interesting selectivity switch was observed with internal alkynes.

Poliomyelitis, caused by poliovirus, is on the verge of eradication, and the world is preparing to shift from live to inactivated polio vaccine. In view of the requirement of non-infectious reagents, especially protein antigens, for surveillance during the final phase of poliovirus eradication, we have attempted to generate reagents that may be of use for the development of diagnostic tests. Polioviral proteins VP0, VP3, VP1, and 3AB were expressed in Escherichia coli using the autoinduction system, purified, and the proteins were used to raise antisera in rabbits. All antisera detected all three serotypes of PV from infected cell lysates in enzyme-linked immunosorbent assay, immunofluorescence and western blotting., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Synthesis of Z-β-aryl-α,β-unsaturated esters from readily available 1-aryl-3-phenoxy propargyl alcohols is achieved via a BF3-mediated syn-selective Meyer-Schuster rearrangement under ambient conditions. The reaction mechanism is postulated to involve an electrophilic borylation of an allene intermediate as the key step to kinetically control the stereoselectivity.

Objectives: The purpose of this study was to assess the impact of manual versus automated contrast injection on renal complications in patients undergoing percutaneous coronary intervention (PCI)., Background: Contrast volume is a major modifiable risk factor for contrast-induced nephropathy (CIN). Automated contrast injector systems (ACIS) are believed to be associated with a reduction in the total volume of contrast media use., Methods: We compared the outcome of 60,884 patients who underwent PCI at 28 hospitals in Michigan in 2008 to 2009 and assessed the outcome of those treated at hospitals that did not use ACIS (n = 24) and compared them with those that used ACIS (n = 4). Propensity matching was used to adjust for baseline differences., Results: The use of ACIS was associated with a statistically significant albeit clinically small difference in the average volume of contrast media use (mean 199 ± 84 ml vs. mean 204 ± 82 ml, p < 0.0001) with no difference in proportion of patients exceeding contrast volume/calculated creatinine clearance ratio of 3 (28.4% vs. 29.1%, p = 0.19). There was no difference in the incidence of CIN (3.11% vs. 3.42%, p = 0.15) or new need for dialysis (0.30% vs. 0.33%, p = 0.54), and these differences remained nonsignificant in propensity matched analysis. In fully adjusted, multivariate logistic analysis, patients treated with ACIS remained as likely to develop CIN (odds ratio: 0.96, 95% confidence interval: 0.83 to 1.11, p = 0.56) or new need for dialysis (odds ratio: 0.83, 95% confidence interval: 0.54 to 1.28, p = 0.40)., Conclusions: Compared with hospitals using manual injection, institutions having ACIS used slightly less amount of contrast with no reduction in CIN. Use of ACIS is unlikely to impact contrast-induced renal complications in patients undergoing PCI., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cu-catalyzed A(3) coupling of ethoxyacetylene, pyrrolidine and salicylaldehydes led to a concomitant cycloisomerization followed by hydrolysis of the resultant vinyl ether to afford coumarins in a cascade process. The reaction proceeded through exclusive 6-endo-dig cyclization and is compatible with halo and keto groups giving coumarins in good to moderate yields.

Bluetongue virus serotype 21 (BTV-21) was originally isolated from Australia, but has now been reported from India, Indonesia, China and Japan. We report the isolation, and sequencing of BTV-21 from India. The complete ORF sequence of VP2 gene of this isolate showed that it is closely related to recent BTV-21 isolates from Japan (93-94% identity), and distantly related to BTV-21 reference strain (86% identity). Our results, along with the available sequences of Japanese isolates, suggest that the currently circulating BTV-21 strains from India and Japan are divergent from the original strain(s) from Australia and shed light on designing molecular diagnostics for the detection of BTV.

Recent incursions of bluetongue virus (BTV) into previously naive geographical areas have emphasised the need to better understand virus movement and epidemiology. Several bluetongue virus (BTV) serotypes are known to exist in India, and some serotype viruses have been isolated. However, the complete genome of not a single isolate is available to date. We report the complete genome sequence of one, and partial sequences of three other Indian isolates of BTV-9. Evolutionary relationships with segment-2 and -6 sequences of BTV isolates around the world, deduced using four different phylogenetic analyses and a similarity programme, show that BTV-9 (Eastern), BTV-9 (Western), and BTV-5 form a triad of equidistant, genetically distinct groups of viruses. The Indian BTV-9 isolates were closely related to Mediterranean and European BTV-9 isolates (Eastern topotype) based on segment-2 and -6 sequences. By contrast, segment-5 analyses clustered the Indian BTV-9 isolates with South African BTV-3 reference strain (98% identity), which belongs to one of the Western types. These results have implications on BTV origin and movement, genotyping, serotyping, and vaccine design.

A series of novel 5-substituted-1-(arylmethyl/alkylmethyl)-1H-indole-2,3-dione-3-(N-hydroxy/methoxy thiosemicarbazone) analogues were synthesized and evaluated for their anti-HIV activity and anti-tubercular activity in both log phase and starved cultures. The compound 2-(1-{[4-(4-chlorophenyl)tetrahydropyrazin-1(2H)-yl]methyl}-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-yliden)-N-(methyloxy)hydrazine-1-carbothioamide (B21) displayed promising activity against the replication of HIV-1 cells (EC(50) 1.69 μM). In anti-mycobacterial screening B21 proved effective in inhibiting the growth of both log phase (MIC 3.30 μM) and starved (MIC 12.11 μM) MTB cultures. Isocitrate lyase enzyme having momentous implication in persistent TB was shown to be inhibited by 1-cyclopropyl-6-fluoro-7-[4-{[5-methyl-3-((Z)-2-{[(methyloxy)amino]carbothioyl}hydrazono)-2-oxo-1H-indol-1(2H)-yl]methyl}tetrahydropyrazin-1(2H)-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (B30) with 63.44% inhibition at 10 mM., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Various 5-nitro-2-furoic acid hydrazones were synthesized and evaluated for in vitro activities against log and starved phase culture of two mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among twenty one compounds, 5-nitro-N'-[(5-nitro-2-furyl)methylidene]-2-furohydrazide (4o) was found to be the most active compound in vitro with MICs of 2.65 and 10.64 microM against log- and starved-phase culture of MTB. Compound 4o also showed good enzyme inhibition of MTB ICL at 10 microM. The docking studies also confirmed the binding potential of the compounds at the ICL active site., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Chronic kidney disease is a major worldwide problem. Although epidemiologic and experimental studies suggest that n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation may prevent or slow the progression of kidney disease, evidence from clinical trials is inconsistent., Objective: The objective was to combine evidence from controlled clinical trials to assess the effect of n-3 LCPUFA supplementation on the change in urine protein excretion (UPE) and on glomerular filtration rate (GFR)., Design: We performed a meta-analysis of clinical trials that tested the effect of n-3 LCPUFA supplementation on UPE, a marker of kidney damage, and on GFR, a marker of kidney function. A random-effects model was used to pool SD effect size (Cohen's d) across studies., Results: Seventeen trials with 626 participants were included in the meta-analysis. Most trials focused on patients with a single underlying diagnosis: IgA nephropathy (n = 5), diabetes (n = 7), or lupus nephritis (n = 1). The dose of n-3 LCPUFAs ranged from 0.7 to 5.1 g/d, and the median follow-up was 9 mo. In the pooled analysis, there was a greater reduction in UPE in the n-3 LCPUFA group than in the control group: Cohen's d for all trials was -0.19 (95% CI: -0.34, -0.04; P = 0.01). In a patient with 1 g UPE/d , this corresponds to a reduction of 190 mg/d. Effects on GFR were reported in 12 trials. The decline in GFR was slower in the n-3 LCPUFA group than in the control group, but this effect was not significant (0.11; 95% CI: -0.07, 0.29; P = 0.24)., Conclusions: In our meta-analysis, use of n-3 LCPUFA supplements reduced UPE but not the decline in GFR. However, small numbers of participants in trials, different methods of assessing proteinuria and GFR, and inconsistent data reporting limit the strength of these conclusions. Large, high-quality trials with clinical outcomes are warranted.

Mitogen-activated protein (MAP) p38 kinase is a serine-threonine protein kinase and its inhibitors are useful in the treatment of inflammatory diseases. Pharmacophore models were developed using HypoGen program of Catalyst with diverse classes of p38 MAP kinase inhibitors. The best pharmacophore hypothesis (Hypo1) with hydrogen-bond acceptor (HBA), hydrophobic (HY), hydrogen-bond donor (HBD), and ring aromatic (RA) as features has correlation coefficient of 0.959, root mean square deviation (RMSD) of 1.069 and configuration cost of 14.536. The model was validated using test set containing 119 compounds and had high correlation coefficient of 0.851. The results demonstrate that results obtained in this study can be considered to be useful and reliable tools in identifying structurally diverse compounds with desired biological activity.

Adenosine receptor A2B (ADoR A2B) is an important G protein-coupled receptor (GPCR) of the rhodopsin family, and plays a pivotal role in gastrointestinal, neurological and hypersensitive disorders. QSAR and pharmacophore studies were carried out using 63 ADoR A2B inhibitor molecules to characterize molecular features and structural requirements for biological interaction. QSAR modelling using genetic algorithm- partial least squares (G/PLS) method identified molecular shape, size electrophilicity and conformational flexibility as important descriptors for these compounds affinity to the receptor. Further analysis of pharmacophore model revealed hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), hydrophobic aliphatic (HY-ala) and hydrophobic aromatic (HY-aro) as the crucial molecular features that predict binding affinity of these compounds to ADoR A2B. These observations provide important insights to the rationale development of novel and potent compounds against ADoR A2B.

Cathepsin K is a lysosomal cysteine protease that is highly and selectively expressed in osteoclasts, the cells which degrade bone during the continuous cycle of bone degradation and formation. Inhibition of cathepsin K represents a potential therapeutic approach for diseases characterized by excessive bone resorption such as osteoporosis. In order to elucidate the essential structural features for cathepsin K, a three-dimensional pharmacophore hypotheses were built on the basis of a set of known cathepsin K inhibitors selected from the literature using catalyst program. Several methods are used in validation of pharmacophore hypothesis were presented, and the fourth hypothesis (Hypo4) was considered to be the best pharmacophore hypothesis which has a correlation coefficient of 0.944 with training set and has high prediction of activity for a set of 30 test molecules with correlation of 0.909. The model (Hypo4) was then employed as 3D search query to screen the Maybridge database containing 59,000 compounds, to discover novel and highly potent ligands. For analyzing intermolecular interactions between protein and ligand, all the molecules were docked using Glide software. The result showed that the type and spatial location of chemical features encoded in the pharmacophore are in full agreement with the enzyme inhibitor interaction pattern identified from molecular docking.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 46 triazafluorenone derivatives, inhibiting metabotropic glutamate receptor subtype 1 (mGluR1). It includes molecular field analysis (MFA) and receptor surface analysis (RSA). The QSAR model was developed using 35 compounds and its predictive ability was assessed using a test set of 11 compounds. The predictive 3D-QSAR models have conventional r(2) values of 0.908 and 0.798 for MFA and RSA, respectively; while the cross-validated coefficient r(cv)(2) values of 0.707 and 0.580 for MFA and RSA, respectively. The results of 3D-QSAR methodologies provide a powerful tool directed to the design of novel and selective triazafluorenone inhibitors.

Our objective was to evaluate the safety of percutaneous transfemoral catheterization performed by way of synthetic aortofemoral vascular grafts. Between 1994 and 2003, 123 catheterization procedures were performed using a synthetic aortofemoral graft (median graft age 2.5 years, range 4 days to 10.3 years), including 63 (51%) interventional and 60 (49%) diagnostic procedures. Adverse events related to vascular access occurred in 7 of 123 procedures (5.7%), including blood transfusion (4.1%), thrombotic occlusion (1.6%), transient limb ischemia (0.8%), and retroperitoneal hemorrhage (0.8%). No deaths, graft infections, or pseudoaneurysms occurred.