Synthesis of DNA interactive C3-trans-cinnamide linked β-carboline conjugates as potential cytotoxic and DNA topoisomerase I inhibitors

  • Bioorg Med Chem. 2018 Sep 15;26(17):4916-4929. doi: 10.1016/j.bmc.2018.08.031.
Manda Sathish  1 ,  Sabanis Chetan Dushantrao  2 ,  Shalini Nekkanti  2 ,  Ramya Tokala  2 ,  Soujanya Thatikonda  3 ,  Yellaiah Tangella  1 ,  Gunda Srinivas  4 ,  Shirisha Cherukommu  4 ,  Namballa Hari Krishna  2 ,  Nagula Shankaraiah  5 ,  Narayana Nagesh  6 ,  Ahmed Kamal  7
Affiliations
  • 1. Medicinal Chemistry & Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
  • 2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
  • 3. Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
  • 4. CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
  • 5. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: [email protected].
  • 6. CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India. Electronic address: [email protected].
  • 7. Medicinal Chemistry & Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110 062, India. Electronic address: [email protected].
PMID: 30172625 DOI: 10.1016/j.bmc.2018.08.031
Abstract

A series of new C3-trans-cinnamide linked β-carboline conjugates has been synthesized by coupling between various β-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human Cancer cell lines such as A549 (lung Cancer), MCF-7 (breast Cancer), B16 (melanoma), HeLa (cervical Cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested Cancer cell lines with IC50 values 13-45 nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05 nM and 13.84 nM respectively) and also even potent on Other cell lines tested. Further, detailed investigations such as cell cycle analysis, Apoptosis induction study, Topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive Topoisomerase I inhibitors.

Keywords
Anticancer activity; DNA intercalation; Topoisomerase I; Trans-cinnamides; β-Carbolines.