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A library of 49 analogs of imidazo[1,2-a]pyridine with 2-halo, aryl, styryl and phenylethynyl-substitution at C-2 position and N-/O-/S-methyl linkage at C-3 position, have been synthesized and evaluated for their anti-proliferative activity against breast (MCF-7, MDA-MB-231), pancreatic (MiaPaca-2), lung (A549), prostate (PC-3) and colon (HCT-116) cancer cell lines and normal cells (HEK-293). Among the screened compounds, 5b exhibited best anticancer potential in all tested cancer cells with IC 50 ranging from 3.5 to 61.1 µM and no toxicity in normal cells. Further, mechanistic study of 5b revealed concentration dependent increased generation of ROS, reduced mitochondrial membrane potential (MMP), surface and nuclear morphological alterations and inhibition of colony formation in HCT-116 cells. Western blot results had shown that the cell death in HCT-116 colon cancer cells was achieved through the induction of apoptosis via upregulation of the PTEN gene and downregulation of AKT pathway. Similarly, 5b treatment induced caspase-3 cleavage which is a hallmark of apoptosis. Molecular docking and binding energy (ΔG) studies of hit 5b with respect to three important cancer targets (EGFR, mTOR and PI3Kα) revealed strong binding of inhibitor with PI3Kα (docking score -6.932 and ΔG -56.297)., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

A strategy of "Nature-to-new" with iterative scaffold-hopping was considered for investigation of privileged ring/functional motif-elaborated analogs of natural aurones. An organocatalyzed umpolung chemistry based method was established for molecular-diversity feasible synthesis of title class of chemotypes i.e. (Z)-2-Arylideneimidazo[1,2-a]pyridinones and (Z)-2-Arylidenebenzo[d]imidazo[2,1-b]thiazol-3-ones. Various biophysical experiments indicated their important biological properties. The analogs showed characteristic anticancer activities with efficiency more than an anticancer drug. The compounds induced apoptosis with arrest in the S phase of the cell cycle regulation. The compounds' significant effect in up/down-regulation of various apoptotic proteins, an apoptosis cascade, and the inhibition of topoisomerases-mediated DNA relaxation process was identified. The analysis of the structure-activity relationship, interference with biological events and the drug-likeness physicochemical properties of the compounds in the acceptable window indicated distinctive medicinal molecule-to-properties of the investigated chemotypes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Two series of (hetero)arylamino-naphthoquinones and benzo-fused carbazolequinones were considered for study with the rationale that related structural motifs are present in numerous drugs, clinical trial agents, natural products and hTopoIIα inhibitors. Total 42 compounds were synthesized by reactions including dehydrogenative CN and Pd-catalyzed CC bond forming transformations. These compounds were screened against numerous cancer cells including highly metastatic one (MCF-7, MDA-MB-231, H-357 and HEK293T), and normal cells (MCF 10A). Some of the active compounds were evaluated for clonogenic cell survival and apoptotic effects in cancer cells (DAPI nuclear staining, Comet assay, Annexin-V-FITC/PI dual staining, flow cytometry, and western blot analysis with relevant proteins). All compounds were tested for hTopoIIα inhibitory activity. The investigated series compounds showed important properties like significant apoptotic antiproliferation in cancer cells with cell cycle arrest at S-phase and downregulation of NF- κβ signaling cascade, relatively less cytotoxicity to normal cells, and hTopoIIα inhibition with more efficiency compared to an anticancer drug etoposide., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

• C-8 spiro-isoxazoline derivatives of andrographolide were synthesised. • 4k displayed most potent cytotoxicity (IC 50 =3 μM) in breast cancer cells (MCF-7). • 4k increased the production of cellular and mitochondrial ROS, decreased the MMP, and inhibited the colony formation. • 4k also induced apoptosis in MCF-7 by attenuating the BCl2 expression in a dose dependent manner. 14-Deoxy-11,12-didehydroandrographolide (14-DDA, 3), a secondary metabolite found in Andrographis paniculata nees , has been synthetically modified into a new series of C-8 spiro-isoxazoline derivatives. Andrographolide and its derivatives were well reported for the anticancer activity so herein we have synthesised C-8 spiro-isoxazoline derivatives (4a-l) and screened for in vitro studies against four human cancer cell lines: breast (MCF-7), lung (A549), pancreatic (MiaPaCa-2), and prostate (PC-3). Most of the synthesized compounds exhibited better anti-cancer activities than the parent natural products andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (3) for different human cancer lines. Among all compounds, compound 4k displayed most potent cytotoxicity (IC 50 =3 μM) in breast cancer cells (MCF-7). Further, mechanistic studies revealed that compound 4k affected the nuclear morphology of MCF-7 cells, increased the production of cellular and mitochondrial ROS, decreased the mitochondrial membrane potential (MMP), and inhibited the colony formation. The compound 4k also induced apoptosis in MCF-7 by attenuating the BCl2 expression in a dose dependent manner. The expression of Cdk-4 was also downregulated by 4k. The overall findings of this study indicate that the compound 4k exhibited significant anticancer activity with reduced toxicity in-vitro and might thus be a promising anti-cancer lead candidate. [ABSTRACT FROM AUTHOR]