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

  • Bioorg Chem. 2022 May;122:105706. doi: 10.1016/j.bioorg.2022.105706.
Manasa Kadagathur  1 ,  Arbaz Sujat Shaikh  1 ,  Biswajit Panda  2 ,  Joel George  3 ,  Regur Phanindranath  3 ,  Dilep Kumar Sigalapalli  1 ,  Nagesh A Bhale  4 ,  Chandraiah Godugu  5 ,  Narayana Nagesh  6 ,  Nagula Shankaraiah  7 ,  Neelima D Tangellamudi  8
Affiliations
  • 1. Department of Medicinal Chemistry, India.
  • 2. Department of Regulatory Toxicology, India.
  • 3. CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEXE II, Uppal Road, Hyderabad, 500007, India.
  • 4. Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India.
  • 5. Department of Regulatory Toxicology, India. Electronic address: [email protected].
  • 6. CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEXE II, Uppal Road, Hyderabad, 500007, India. Electronic address: [email protected].
  • 7. Department of Medicinal Chemistry, India. Electronic address: [email protected].
  • 8. Department of Medicinal Chemistry, India. Electronic address: [email protected].
PMID: 35240414 DOI: 10.1016/j.bioorg.2022.105706
Abstract

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 IC50 values < 4 μM with the best cytotoxicity and a 13-fold selectivity towards lung Cancer cells (IC50 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.

Keywords
Anticancer; DNA intercalation; Indoloazepinone; Molecular modeling; Oxindole; Pyrroloazepinone; Topoisomerase I inhibition.
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