Synthesis and cytotoxicity of azaheterocyclic compounds

Multicomponent coupling reactions (MCRs) have been known for a long time and one such reaction that utilizes isocyanides is Passerini reaction. It is a powerful tool to synthesize libraries of different compounds. Azaheterocyclic compounds play an important role in medicinal chemistry. Motifs such as imidazoles, piperazines, pyrazoles, pyridines, triazoles, etc. are routinely observed in several compounds of pharmacological interest. Several natural products also contain these motifs in them. We have undertaken a library synthesis of heterocyclic molecules driven by our group\u27s long-standing interest of synthesizing medicinally relevant small molecules employing green chemistry techniques. This thesis details our efforts on the development of novel synthetic methodologies for the synthesis of functionalized azaheterocyclic compounds as potential anti-cancer agents. We initiated the synthesis of these compounds employing Passerini reaction as the key step. The biological evaluation of these synthetic derivatives showed some promise as anti-cancer agents

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Studies on organocatalytic asymmetric Michael addition reactions

The development of organocatalysts for asymmetric synthesis continues to be actively investigated in recent years due to the advantages over conventional metal-based catalysts. Research in our laboratory has focused on the development of organocatalysts for fundamental carbon-carbon bond forming reactions, such as the Michael addition reaction. -- The organocatalytic Michael addition of ketones to nitroalkenes is of special interest since the reaction generates two contiguous stereocenters and the products (γ-nitro ketones) are useful synthetic intermediates. We have observed that this reaction is efficiently catalyzed by pyrrolidine-based chiral, secondary diamines as well as triamines. The use of a protic acid in conjunction with the amine catalyst is beneficial and the Michael addition products (syn diastereomers) are obtained with excellent enantioselectivities (up to 99% ee) and diastereoselectivity (up to 50:1 dr) for cyclic ketones and nitroalkenes derived from aromatic aldehydes. Details regarding the effect of changes in the catalyst and protic acid structure, variation of catalyst/protic acid combinations and the scope of the reaction with respect to structural changes in the ketone and nitroalkenes will be discussed. -- In addition, the application of the chiral triamines in Michael reactions involving iminium ion intermediates has been examined. Preliminary results from these studies will be presented. The attempted synthesis of pyrrolidine-based organocatalysts with guanidine-containing side chains as well as catalysts based on the camphor scaffold will also be presented

Design & Synthesis of InCl₃ Catalyzed Novel Pyrazole Conjugates with 2^°-Amines; Discover Their in Vitro Antimicrobial & DFT Studies

A mild and efficient protocol was developed for the synthesis of pyrazole and 2°-amine hybrid conjugates through an InCl3 Ugi four-component reaction followed by a base mediated secondary amine coupling reaction. MCRs have been used extensively in the field of combinatorial chemistry, which offers the synthesis of libraries of similar molecules in a parallel fashion. A small library of novel N-allyl-N-(1-(4-(aminomethyl) phenyl)-2-(tert-butylamino)-2-oxoethyl)-1,3-diphenyl-1H-pyrazole-4-carboxamide scaffold was designed and synthesized through a one-pot four-component Ugi reaction, the resulting Ugi product pyrazole derivative coupled with various secondary amines to prepare target pyrazole – amine conjugate molecules. The structures of synthesized conjugates confirmed by spectroscopic techniques (NMR, C, H, N analysis, and MS). The in vitro antimicrobial survey of these pyrazole-secondary amine conjugates was supported by DFT studies; thereby notifies the conjugates are promising antimicrobial agents and are comparable to the standard antimicrobial molecules such as ampicilin, griseofulvin, isoniazide and rifampicin.</p

A comparative study of PD-L1 IHC assays using immune cell scoring and CPS in breast cancer.

e15262 Background: The clinical benefit of immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death ligand 1 (PD-L1) pathway has previously been demonstrated across a range of tumor types, including in PD-L1+ patients with metastatic triple-negative breast cancer (TNBC). Various PD-L1 immunohistochemistry (IHC) assays and scoring algorithms are being investigated to select patients with breast cancer (BC) most likely to respond to ICIs. Scoring algorithms include PD-L1 expression on tumor cells, immune cells (ICs), or both. We compared the analytical concordance of 3 PD-L1 IHC assays and evaluated PD-L1+ prevalence, using combined positive score (CPS) and % IC scoring algorithms in commercially procured TNBC and hormone receptor–positive, HER2-negative (HR+/HER2−) BC samples. Methods: PD-L1 expression was assessed by HistoGeneX (Naperville, IL) in 163 commercially procured, surgically resected, formalin-fixed, paraffin-embedded BC samples (mostly stage I–III) using the Ventana PD-L1 (SP142) and Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays in conjunction with the CPS (28-8 and 22C3 assays) and % IC algorithms (SP142 and 28-8 assays). PD-L1+ prevalence with each assay and concordance between assays were calculated using CPS ≥ 1 and IC ≥ 1% cutoffs, with a single pathologist assigned to each scoring algorithm. Results: 93 HR+/HER2− BC and 70 TNBC samples were evaluable for PD-L1 expression across all assays and algorithms. Overall concordance was higher between the 28-8 and 22C3 assays (CPS cutoff of 1) than between the 28-8 and SP142 assays (IC cutoff of 1%). PD-L1+ prevalence was similar with the 28-8 and 22C3 assays (CPS ≥ 1) and higher with the 28-8 assay (IC ≥ 1%) than with the SP142 assay (IC ≥ 1%). PD-L1+ samples identified by the SP142 assay (IC ≥ 1%) were mostly included within PD-L1+ sample sets defined by the 28-8 assay (IC ≥ 1% and CPS ≥ 1). PD-L1+ prevalence was higher in TNBC vs HR+/HER2− BC for all assays (Table). No clear trend in PD-L1+ prevalence was observed across tumor grade and stage. Conclusions: High analytical concordance was observed between the 28-8 and 22C3 assays (CPS cutoff of 1) in both HR+/HER2− BC and TNBC samples. PD-L1+ prevalence varied according to IHC assay, scoring algorithm, and cutoff used. Further studies are needed to select the most appropriate PD-L1 assay and scoring algorithm for BC clinical trials. [Table: see text] </jats:p