Synthesis of indolo/pyrroloazepinone-oxindoles as potential cytotoxic, DNA-intercalating and Topo I inhibitors.

[Display omitted] • 14d displayed exceptional cytotoxicity against the A549 cells with an IC 50 = 2.33 μM. • Dose-dependent apoptosis was induced by compound 14d. • Intercalative mode of binding with DNA and topoisomerase I inhibition was exhibited. • In vitro results were corroborated by in silico molecular modeling studies. A series of 17 indolo/pyrroloazepinone-oxindole conjugates was synthesized and evaluated for their antiproliferative activity against a panel of selected human cancer cell lines including A549 (lung cancer), HCT116 (colon cancer), MCF7 (breast cancer), and SK-MEL-28 (melanoma). Among the synthesized molecules (14a - m and 15a - d), compound 14d displayed remarkable activity against A549, HCT116 and SK-MEL-28 cells with IC 50 values < 4 μM with the best cytotoxicity and a 13-fold selectivity towards lung cancer cells (IC 50 value of 2.33 μM) over the normal rat kidney cells (NRK). Further, 14d -mediated apoptosis affected the cellular and nuclear morphology of the cancer cells in a dose-dependent manner. Wound healing and clonogenic assays inferred the inhibition of cell growth and migration. Target-based studies of compound 14d corroborated its DNA-intercalative capability and Topo I inhibitory activity which have been fortified by molecular modeling studies. Finally, the drug-likeness of the potent compound was determined by performing in silico ADME/T prediction studies. [ABSTRACT FROM AUTHOR]