Cytotoxic Effect of New (E)‐2‐Cyano‐N‐(tetrahydrobenzo[b]thiophen‐2‐yl)acrylamide Derivatives: Down‐Regulation of RBL2 and STAT2 and Triggering of DNA Damage in Breast Carcinoma

Abstract

A novel series of 2‐cyano‐N‐(tetrahydrobenzo[b]thiophen‐2‐yl)acrylamide derivatives were synthesized and their structures were confirmed using several spectral tools. All compounds were subjected to MTT assay to elucidate their cytotoxic effect against human hepatocellular carcinoma (HEPG2), human Caucasian breast adenocarcinoma (MCF7), human pancreatic cancer cell line (PACA2), human prostate cancer cell line (PC3), and normal skin fibroblast (BJ1). Among them, the acrylamide derivatives 5, 10 and 14 exerted potent activities against MCF7 with IC50 values of 61.2, 66.4, and 55.3 μg/ml respectively. A molecular docking was performed to study the possibility of the molecular binding of these three compounds with the active site of signal transducer and activator of transcription 1 protein (STAT1). Gene expression analysis demonstrated the significant down‐regulation of RBL2 (RB transcriptional corepressor like 2) and STAT2 (Signal transducer and activator of transcription 2) in treated MCF7 cells and also showed the significant effect in down‐regulating KRAS (Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog) and SMAD (Sma and Mad proteins) genes in PC3 cells. Comet assay revealed the best effect of Ethyl 2‐(2‐cyano‐3‐(3,4‐dimethoxyphenyl)acrylamido)‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate in damaging the DNA of MCF7 cells (18.75±1.50 %). Also, DNA fragmentation was studied electrophoretically, which confirmed the results of the comet assay.

Novel Scaffolds Based on Bis-thiazole Connected to Quinoxaline or Thienothiophene through 2-Phenoxy-N-arylacetamide Groups as New Hybrid Molecules: Synthesis, Antibacterial Activity, and Molecular Docking Investigations

“…The pharmacophore scaffolds of several compounds are combined to create hybrid molecules. In this regard, anticancer drugs that are safer and more effective than those presently on the market may benefit from hybridization. , In light of these findings, as well as our continuing interest in the synthesis of heterocycles − and their bis­(heterocycles), − we sought to incorporate N -arylacetamide units into the backbone of thiazole to obtain a novel series of bis-thiazole derivatives linked through biologically active quinoxaline or thienothiophene cores using a “hybrid conjugation of bioactive ligands” approach. Our synthetic strategy employs 2-(4-(1-(2-carbamothioylhydrazineylidene)­ethyl)­phenoxy)- N -(aryl)­acetamides, 2-(4-(2-bromoacetyl)­phenoxy)- N -(aryl)­acetamides, bis­(4,1-phenylene)­bis­(2-bromoethan-1-ones) 7 , bis­(α-bromoketone), and bis­(thiosemicarbazone) as precursors (Figure ).…”