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

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

  • Bioorg Med Chem Lett. 2015 Oct 1;25(19):4239-44. doi: 10.1016/j.bmcl.2015.07.100.
Nagula Shankaraiah 1,  Niggula Praveen Kumar 2,  Suresh Babu Amula 3,  Shalini Nekkanti 3,  Manish Kumar Jeengar 4,  V G M Naidu 5,  T Srinivasa Reddy 6,  Ahmed Kamal 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: shankar@niperhyd.ac.in.
  • 2 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.
  • 3 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
  • 4 Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
  • 5 Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: vgmnaidu@niperhyd.ac.in.
  • 6 Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
  • 7 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: ahmedkamal@iict.res.in.
PMID: 26292628 DOI: 10.1016/j.bmcl.2015.07.100
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.

Keywords

Azido reduction; Cell cycle analysis; Cytotoxicity; Molecular modeling; Podophyllotoxin; Sodium iodide; Sulfamic acid; Thiourea; Topoisomerase-II inhibition.

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