One-pot synthesis of podophyllotoxin-thiourea congeners by employing NH₂SO₃H/NaI: Anticancer activity, DNA topoisomerase-II inhibition, and apoptosis inducing agents.

Abstract

A facile one-pot method for the synthesis of novel podophyllotoxin-thiourea congeners has been developed by using NH2SO3H/NaI system. Interestingly, 4β-azido podophyllotoxin reduction with concomitant aryl isothiocyanates coupling under mild reaction conditions has been achieved. These compounds have been investigated for their in vitro cytotoxicity against A549, MDA MB-231, DU-145, LNCaP, and HGC-27 cancer cell lines. Some of the representative compounds have selectively exhibited cytotoxicity on DU-145 (human prostate cancer) cells and the most potent compound was 4a (IC50 of 0.50 ± 0.03 μM) with optimal safety therapeutic window (81.7 fold) on normal human prostate cell line (RWPE-1, IC50 of 40.85 ± 0.78). The flow-cytometric analysis of the compound 4a in prostate cancer cells indicated a strong G2/M-phase arrest and significant topoisomerase II inhibition activity. Furthermore, these compounds induce apoptosis as observed by Acridine Orange and Ethidium Bromide (AO/EB) staining and Annexin V binding assay. Molecular docking results of the title compounds with topoisomerase-IIα were presented as theoretical support for the experimental data.

• Authors: Nagula Shankaraiah, Niggula Praveen Kumar, Suresh Babu Amula, Shalini Nekkanti, Manish Kumar Jeengar, V G M Naidu, T Srinivasa Reddy, Ahmed Kamal
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 19 Pg. 4239-44 (Oct 01 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26292628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Amides
• Antineoplastic Agents
• Sulfur Oxides
• Topoisomerase II Inhibitors
• DNA Topoisomerases, Type II
• Sodium Iodide
• Thiourea
• sulfur trioxide
• Podophyllotoxin

Topics

• Amides (chemistry)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Topoisomerases, Type II (metabolism)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Molecular Structure
• Podophyllotoxin (chemistry, pharmacology)
• Sodium Iodide (chemistry)
• Structure-Activity Relationship
• Sulfur Oxides (chemistry)
• Thiourea (chemistry, pharmacology)
• Topoisomerase II Inhibitors (chemical synthesis, chemistry, pharmacology)