2. Academic Validation
  3. Design and synthesis of 1,2,3-triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates as tubulin polymerization inhibitors

Design and synthesis of 1,2,3-triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates as tubulin polymerization inhibitors

  • Bioorg Med Chem. 2017 Jul 1;25(13):3285-3297. doi: 10.1016/j.bmc.2017.04.013.
Siddiq Pasha Shaik 1,  M V P S Vishnuvardhan 2,  Faria Sultana 2,  A V Subba Rao 1,  Chandrakant Bagul 3,  Debanjan Bhattacharjee 4,  Jeevak Sopanrao Kapure 3,  Nishant Jain 4,  Ahmed Kamal 5
Affiliations

Affiliations

  • 1 Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India; Academy of Scientific and Innovative Research, New Delhi 110 025, India.
  • 2 Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India.
  • 3 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India.
  • 4 Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India.
  • 5 Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India; Academy of Scientific and Innovative Research, New Delhi 110 025, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India; Catalytic Chemistry Research Chair, Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: ahmedkamal@iict.res.in.
PMID: 28462842 DOI: 10.1016/j.bmc.2017.04.013
Abstract

1,2,3-Triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates (5a-v) were designed, synthesized and evaluated for their cytotoxic potency against some human Cancer cell lines like DU-145 (prostate), HeLa (cervical), MCF-7 (breast) HepG2 (liver) and A549 (lung). Preliminary results revealed that some of these conjugates like 5f and 5k exhibited significant antiproliferative effect against human breast Cancer cells (MCF-7) with IC50 values of 0.60 and 0.78µM respectively. Flow cytometric analysis of the cell cycle demonstrated an increase in the percentage of cells in the G2/M phase which was further authenticated by elevation of cyclin B1 protein levels. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 5f and 5k, and western blot analysis revealed that these conjugates accumulated more tubulin in the soluble fraction. Moreover, the conjugates caused Apoptosis of the cells that was confirmed by mitochondrial membrane potential and Annexin V-FITC assay. Molecular docking studies indicated that these conjugates occupy the colchicine binding site of the tubulin protein.

Keywords

1,2,3-Triazole; Apoptosis; Benzo[d]imidazo[2,1-b]thiazole; Cytotoxicity; Tubulin depolymerization.

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