Novel cyanochalcones as potential anticancer agents: apoptosis, cell cycle arrest, DNA binding, and molecular docking studies

In the light of anticancer drug discovery and development, a new series of cyanochalcones incorporating indole moiety (5a-g) were efficiently synthesized and characterized by different spectral analysis. MTT assay was used to evaluate the antiproliferative activity of the synthesized compounds towards different cancer cells (Hela, MDA-MB-231, A375, and A549) in parallel with normal cells (HSF). Trimethoxy and diethoxy-containing derivatives (5d and 5e) displayed the most selective cytotoxic activities against cervical Hela cells with IC50 values of 8.29 and 11.82 µM, respectively, with great safety pattern toward normal HSF cells (Selectivity index: 21.3 and 13.9, respectively). Therefore, 5d and 5e were chosen to study their effects on apoptosis, cell cycle arrest, and migration of Hela cells using flow cytometric analysis and wound healing assay. They induced apoptosis and cell cycle arrest at the S phase and impaired migration of HeLa cells. Regarding their effects on the expression profile of crucial genes related to the potential anticancer activities, 5d and 5e remarkably upregulated caspase 3 and Beclin1 and downregulated cyclin A1, CDK2, CDH2, MMP9, and HIF1A using qRT-PCR and ELISA techniques. UV–Vis spectral measurement demonstrated the ability of 5d and 5e to bind CT-DNA efficiently with Kb values of 3.7 × 105 and 1 × 105 M−1, respectively. Moreover, in silico molecular docking was performed to assess the binding affinities of the compounds toward the active sites of Bcl2, CDK2, and DNA. Therefore, cyanochalcones 5d and 5e might be promising anticancer agents and could offer a scientific basis for intensive research into cancer chemotherapy. Communicated by Ramaswamy H. Sarma A novel series of cyanochalcones incorporating indole moiety (5a–g) were designed and synthesized.Cytotoxic activities of the designed compounds were evaluated in vitro against different human cancer cell lines (Hela, MDA-MB-231, A375, and A549) in parallel with human normal cells (HSF).5d and 5e stimulated apoptosis (through deregulating Bcl2 and upregulating Cas3), cell cycle arrest at the S phase (by suppressing cyclin A and CDK2), and inhibited migration (through downregulating CDH2 and MMP9) of Hela cells.5d and 5e demonstrated good DNA binding affinities.Molecular docking was carried out to confirm the binding abilities of 5d and 5e toward Bcl2, CDK2, and DNA. A novel series of cyanochalcones incorporating indole moiety (5a–g) were designed and synthesized. Cytotoxic activities of the designed compounds were evaluated in vitro against different human cancer cell lines (Hela, MDA-MB-231, A375, and A549) in parallel with human normal cells (HSF). 5d and 5e stimulated apoptosis (through deregulating Bcl2 and upregulating Cas3), cell cycle arrest at the S phase (by suppressing cyclin A and CDK2), and inhibited migration (through downregulating CDH2 and MMP9) of Hela cells. 5d and 5e demonstrated good DNA binding affinities. Molecular docking was carried out to confirm the binding abilities of 5d and 5e toward Bcl2, CDK2, and DNA.</p

Synthesis of dihydropyridine, fused dihydropyridines and benzo[4,5]imidazo[2,1-<i>b</i>]quinazolines linked to ester and amide moieties <i>via</i> a benzene ring as new hybrid molecules

A series of novel 2-oxo-2-(arylamino)ethyl 4-formylbenzoates were prepared via the reaction of the potassium salt of p-formylbenzoic acid with 2-chloro-N-aryl-acetamide in DMF at reflux. A new series of 1,4-dihydropyridin-3,5-dicarbonitriles, hexahydroacridine-1,8-diones, decahydropyrimido[4,5-b]quinolines, and hexahydrobenzo[4,5]imidazo[2,1-b]quinazolines which are linked to N-aryl-benzoyloxyacetamide were obtained through the Hantzsch reaction of various 2-oxo-2-(arylamino)ethyl 4-formylbenzoate with the respective 3-aminocrotononitrile or a mixture of 1,3-dicarbonyl compounds and amine source. The structures of the novel compounds were confirmed using a variety of spectra. </p

Hantzsch-like three-component synthesis of <i>bis</i>(1,4-dihydropyridines) and <i>bis</i>(fused-1,4-dihydropyridines) linked to piperazine core <i>via</i> 2-phenoxyethanone linkage: Novel hybrid molecules

The molecular hybridization of various compounds with known pharmacological activity is a particularly popular approach for the development of potential drugs with improved pharmacokinetic profiles. In this respect, a novel series of bis(1,4-dihydropyridine-3,5-dicarbonitrile), bis(decahydroacridine), bis(tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridin), and bis(tetrahydropyrimido[4,5-b]quinoline-2,4,6-trione) derivatives linked to piperazine core via phenoxyethanone linkages were prepared via Hantzsch like reaction of the ((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))dibenzaldehydes, with the appropriate active methylene containing reagents. Attempted synthesis of the target products via bis-alkylation of the appropriate phenol with 1,1′-(piperazine-1,4-diyl)bis(2-chloroethan-1-one) in different basic conditions were unsuccessful. </p