Synthesis and cytotoxicity evaluation of DNA-interactive beta-carboline indolyl-3-glyoxamide derivatives: Topo-II inhibition and in silico modelling studies

In a quest for effective cancer targeted drug therapy, a series of new beta-carboline tethered indole-3-glyoxylamide derivatives, conjoining salient pharmacophoric properties with prominent cytotoxicity, were synthesized. The in vitro cytotoxic ability of the compounds was established, and many of the compounds exhibited remarkable cytotoxicity (IC50 < 10 mu M) on human cancer cell lines like HCT116, A549, SK-MEL-28, and MCF7. Precisely, compound 12x expressed the best cytotoxic potential against melanoma cancer cell line (SK-MEL-28) with an IC50 value of 4.37 mu M. In addition, cytotoxicity evaluation against normal kidney cell line (NRK52E) entrenched the cytospecificity and selectivity index of 12x. The traditional apoptosis assays advised morphological and nuclear alterations such as apoptotic body formation, condensed/horseshoe-shaped/fragmented nuclei, and generation of ROS. The flow cytometric analysis revealed significant early and slight late-stage induction of apoptosis. The target-based physiochemical assays indicated the ability of compound 12x to bind with DNA and inhibition of Topoisomerase II. Moreover, molecular modeling studies affirm the excellent DNA intercalation potential and stabilized interactions of 12x with DNA base pairs. In silico prediction of physicochemical pa-rameters revealed the promising drug-like properties of the synthesized derivatives.

Automated summary

In this study, a series of new beta-carboline tethered indole-3-glyoxylamide derivatives were synthesized, which showed significant pharmacological properties and prominent cytotoxicity. The compounds exhibited remarkable cytotoxicity against human cancer cell lines, especially melanoma, and showed selective toxicity towards cancer cells compared to normal cells. The compounds induced apoptosis and showed potential as DNA binders and inhibitors of Topoisomerase II. Molecular modeling studies confirmed their excellent DNA intercalation potential. In addition, in silico analysis predicted the promising drug-like properties of the synthesized derivatives.