4β-[4'-(1-(Aryl)ureido)benzamide]podophyllotoxins as DNA topoisomerase I and IIα inhibitors and apoptosis inducing agents

  • Bioorg Med Chem. 2013 Sep 1;21(17):5198-208. doi: 10.1016/j.bmc.2013.06.033.
Ahmed Kamal  1 ,  Paidakula Suresh ,  M Janaki Ramaiah ,  T Srinivasa Reddy ,  Ravi Kumar Kapavarapu ,  Bolla Narasimha Rao ,  Syed Imthiajali ,  T Lakshminarayan Reddy ,  S N C V L Pushpavalli ,  Nagula Shankaraiah ,  Manika Pal-Bhadra
Affiliations
  • 1. Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. [email protected]
PMID: 23849207 DOI: 10.1016/j.bmc.2013.06.033
Abstract

A series of 4β-[4'-(1-(aryl)ureido)benzamide]podophyllotoxin congeners (11a-l) were synthesized and evaluated for their cytotoxic activity against six human Cancer cell lines. Some of the compounds like 11a, 11h, 11k and 11l showed significant anti-proliferative activity in Colo-205 cells and were superior to etoposide. The flow-cytometric analysis studies indicated that these compounds show strong G1 cell cycle arrest, as well exhibited improved inhibitory activities on DNA Topoisomerase I and IIα Enzymes. These compounds induce Apoptosis by up regulating Caspase-3 protein as observed by ELISA and Western blotting analysis. In addition, a brief structure-activity relationship studies within the series along with docking results of representative compounds 11a, 11h, 11k, 11l were presented.

Keywords
Cell cycle; Cytotoxicity; Etoposide; Podophyllotoxin; Topoisomerase-I enzyme; Topoisomerase-IIα enzyme.