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
  • 1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.