4β-amidotriazole linked podophyllotoxin congeners: DNA topoisomerase-IIα inhibition and potential anticancer agents for prostate cancer

V. Ganga Reddy, Srinivasa Reddy Bonam, T. Srinivasa Reddy, Ravikumar Akunuri, V. G.M. Naidu, V. Lakshma Nayak, Suresh K. Bhargava, H. M.Sampath Kumar, P. Srihari, Ahmed Kamal

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Topoisomerases (topo-I and topo-II) have occupied a significant role in DNA replication, transcription, and are a promising set of antitumor targets. In the present approach, a series of new 4β-amidotriazole linked podophyllotoxin derivatives (10a-i and 11a-k) were designed, synthesized by employing the click chemistry and their biological activities were evaluated. The majority of derivatives showed promising antiproliferative activity with IC50 values ranging from 1 to 10 μM on the six human cancer cell lines; cervical (HeLa), breast (MCF-7), prostate (DU-145), lung (A549), liver (HepG2) and colon (HT-29). Among them, some of the congeners 10b, 10g and 10i have shown remarkable cytotoxicity with IC50 values of, < 1 μM against the tested cancer cell lines and found to be more active than etoposide. Topoisomerase-mediated DNA relaxation assay results showed that the derivatives could efficiently inhibit the activity of topoisomerase-II. In addition, flow cytometry analysis on DU-145 cells revealed that these compounds arrest G2/M phase of cell cycle. Further apoptotic studies were also performed on these DU-145 cells, which showed that this class of compounds could induce apoptosis effectively.

Original languageEnglish (US)
Pages (from-to)595-611
Number of pages17
JournalEuropean journal of medicinal chemistry
Volume144
DOIs
StatePublished - Jan 20 2018
Externally publishedYes

Keywords

  • Anticancer activity
  • Apoptosis
  • Cell cycle
  • Topo-II inhibition
  • Triazole

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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