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

  • Eur J Med Chem. 2018 Jan 20:144:595-611. doi: 10.1016/j.ejmech.2017.12.050.
V Ganga Reddy  1 ,  Srinivasa Reddy Bonam  2 ,  T Srinivasa Reddy  3 ,  Ravikumar Akunuri  4 ,  V G M Naidu  4 ,  V Lakshma Nayak  5 ,  Suresh K Bhargava  6 ,  H M Sampath Kumar  2 ,  P Srihari  7 ,  Ahmed Kamal  8
Affiliations
  • 1. Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India.
  • 2. Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Vaccine Immunology Laboratory, Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India.
  • 3. Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO BOX 2476, Melbourne, 3001, Australia. Electronic address: [email protected].
  • 4. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India.
  • 5. Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India.
  • 6. Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO BOX 2476, Melbourne, 3001, Australia.
  • 7. Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India. Electronic address: [email protected].
  • 8. Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India; School of Pharmaceutical Education and Research, Jamia Hamdard University, New Delhi, 110062, India. Electronic address: [email protected].
PMID: 29289884 DOI: 10.1016/j.ejmech.2017.12.050
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.

Keywords
Anticancer activity; Apoptosis; Cell cycle; Topo-II inhibition; Triazole.