2. Academic Validation
  3. Synthesis and biological evaluation of podophyllotoxin congeners as tubulin polymerization inhibitors

Synthesis and biological evaluation of podophyllotoxin congeners as tubulin polymerization inhibitors

  • Bioorg Med Chem. 2014 Oct 1;22(19):5466-75. doi: 10.1016/j.bmc.2014.07.031.
Ahmed Kamal 1,  T Srinivasa Reddy 2,  Sowjanya Polepalli 3,  Nekkanti Shalini 4,  V Ganga Reddy 5,  A V Subba Rao 5,  Nishant Jain 3,  Nagula Shankaraiah 4
Affiliations

Affiliations

  • 1 Medicinal Chemistry and 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. Electronic address: ahmedkamal@iict.res.in.
  • 2 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
  • 3 Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
  • 4 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
  • 5 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
PMID: 25131956 DOI: 10.1016/j.bmc.2014.07.031
Abstract

A series of new podophyllotoxin derivatives containing structural modifications at C-7, C-8, and C-9 were synthesized and evaluated for their cytotoxic activity against three human Cancer cell lines. All the synthesized compounds showed significant growth inhibition with GI50 values in micromolar levels while some of the compounds were several times more potent against MCF-7 and HeLa cell lines than MIAPACA cell line. Three compounds (12a, 12d and 12e) emerged as potent compounds with broad spectrum of cytotoxic activity against all the tested cell lines with GI50 values in the range of 0.01-2.1 μM. These compounds induce microtubule depolymerization and arrests cells at the G2/M phase of the cell cycle. Moreover, compounds 12d and 12e disrupted microtubule network and accumulated tubulin in the soluble fraction in a similar manner to their parent podophyllotoxin scaffold. In addition, structure activity relationship studies within the series were also discussed. Molecular docking studies of these compounds into the colchicine-binding site of tubulin, revealed possible mode of inhibition by these compounds.

Keywords

Benzimidazole; Cytotoxicity; Molecular docking; Podophyllotoxin; Tubulin polymerization.

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