Synthesis, molecular docking, and anticancer effect of newly synthesized 2- (thiophen-2-yl)-1H-indole derivatives: suppression of HCT-116 Cell proliferation, cell cycle arrest and downregulation of miR-25, C-Myc and IL-6

Abstract

Abstract In the present study, we prepared new sixteen different derivatives. The first series were prepared (methylene)bis(2-(thiophen-2-yl)-1H-indole) derivatives which have (indole and thiophene rings) by excellent yield from the reaction (2 mmol) 2-(thiophen-2-yl)-1H-indole and (1 mmol) from aldehyde. The second series were synthesized (2-(thiophen-2-yl)-1H-indol-3-yl) methyl) aniline derivatives by at a relatively low yield from multicomponent reaction of three components 2-(thiophen-2-yl)-1H-indole, N-methylaniline and desired aldehydes. The anticancer effect of the newly synthesized derivatives was determined against different cancers, colon, lung, breast and skin. The counter screening was done against normal Epithelial cells (RPE-1). The effect on cell cycle and mechanisms underlying the antitumor effect were also studied. The initial single dose (100µg/ml) testing for all new compounds against this panel of 5 human tumor cell lines indicated that the compounds under investigation exhibited selective cytotoxicity against HCT-116 cell line and compounds (4g, 4a, 4c) showed potent anticancer activity against HCT-116 cell line with an IC50 values of 3.566, 5.087, 6.183 µg/ml respectively. Also, the active derivatives caused cell cycle arrest at the S and G2/M phase with significant(p < 0.0001) increase in the expression levels of tumor suppressors miR-30C, and miR-107 and a tremendous decrease in oncogenic miR-25, IL-6 and C-Myc levels. It is to conclude that the anticancer activity could be through direct interaction with tumor cell DNA like S-phase-dependent chemotherapy drugs. Which can interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil and which were highly effective in killing the cancer cells. This data ensures the efficiency of the 3 analogues on inducing cell cycle arrest and preventing cancer cell growth. The altered expressions explained the molecular mechanisms through which the newly synthesized analogues exert their anticancer action.