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

A series of 17 indolo/pyrroloazepinone-oxindole conjugates was synthesized and evaluated for their anti-proliferative 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 IC50 values < 4 mu M with the best cytotoxicity and a 13-fold selectivity towards lung cancer cells (IC50 value of 2.33 mu M) 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.

Automated summary

A series of new compounds were synthesized and evaluated for their anti-tumor activity. Compound 14d showed remarkable activity against multiple cancer cell lines and exhibited selectivity towards lung cancer cells. Further studies revealed that compound 14d inhibited the growth and migration of cancer cells by interacting with DNA and inhibiting Topo I.