One-pot synthesis of podophyllotoxin–thiourea congeners by employing NH2SO3H/NaI: Anticancer activity, DNA topoisomerase-II inhibition, and apoptosis inducing agents. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Shankaraiah, Nagula; Kumar, Niggula Praveen; Amula, Suresh Babu; Nekkanti, Shalini; Jeengar, Manish Kumar; Naidu, V.G.M.; Reddy, T. Srinivasa; Kamal, Ahmed
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4239
• Page End: 4244
• Publication Date: 2015-10-01
• Subjects: Azido reduction -- Sulfamic acid -- Sodium iodide -- Podophyllotoxin -- Thiourea -- Cell cycle analysis -- Cytotoxicity -- Topoisomerase-II inhibition -- Molecular modeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.07.100
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A facile one-pot method for the synthesis of novel podophyllotoxin–thiourea congeners has been developed by using NH2 SO3 H/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 was4a (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 compound4a 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.