2. Academic Validation
  3. Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents

Synthesis and biological evaluation of arylcinnamide linked combretastatin-A4 hybrids as tubulin polymerization inhibitors and apoptosis inducing agents

  • Bioorg Med Chem Lett. 2016 Jun 15;26(12):2957-2964. doi: 10.1016/j.bmcl.2016.03.049.
Ahmed Kamal 1,  Shaik Bajee 2,  Vadithe Lakshma Nayak 2,  Ayinampudi Venkata Subba Rao 2,  Burri Nagaraju 2,  Challa Ratna Reddy 2,  Kapure Jeevak Sopanrao 3,  Abdullah Alarifi 4
Affiliations

Affiliations

  • 1 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India; Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: ahmedkamal@iict.res.in.
  • 2 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
  • 3 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
  • 4 Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
PMID: 27161282 DOI: 10.1016/j.bmcl.2016.03.049
Abstract

A series of new molecules have been designed based on a hybridization approach by combining the arylcinnamide and combretastatin pharmacophores. These were synthesized and evaluated for their cytotoxic activity, effect on inhibition of tubulin polymerization and Apoptosis inducing ability. Most of the conjugates exhibited significant cytotoxic activity against some representative human Cancer cell lines and two of the conjugates 6i and 6p displayed potent cytotoxicity with GI50 values of 56nM and 31nM respectively against the human breast Cancer cell line (MCF-7). SAR studies revealed that 3,4-substitution on the phenyl ring of the cinnamide moiety is beneficial for enhanced cytotoxicity. Moreover, G2/M cell cycle arrest was induced by these conjugates (6i and 6p) apart from tubulin polymerization inhibition (IC50 of 1.97μM and 1.05μM respectively). Further, mitochondrial membrane potential, Annexin V-FITC and caspase-9 activation assays suggested that these conjugates induce cell death by Apoptosis. Docking studies revealed that these conjugates interact and bind at the colchicine binding site of the tubulin.

Keywords

CA-4; Cell cycle; Cinnamides; Conjugate; Cytotoxicity; Tubulin polymerization.

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