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

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 2016;25(19):4239-44

PMID: 26292628

Full Text on Elsevier Science View on PubMed

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.

Address: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: [email protected].; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India; Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: [email protected].; Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India; Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. Electronic address: [email protected].

DOI: 10.1016/j.bmcl.2015.07.100

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MeSH Terms: Amides, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cell Proliferation, DNA Topoisomerases, Type II, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Podophyllotoxin, Sodium Iodide, Structure-Activity Relationship, Sulfur Oxides, Thiourea, Topoisomerase II Inhibitors