Design and Synthesis of New Tubulin Polymerization Inhibitors Inspired from Combretastatin A-4

Posted: 11 Feb 2020

See all articles by Akanksha Sharma

Akanksha Sharma

Central University of Karnataka

Umesh Prasad Yadav

Central University of Punjab

Sandeep Singh

Central University of Punjab

Harish Holla

Central University of Karnataka

Date Written: February 8, 2020

Abstract

This poster presents the synthesis of a series of tubulin polymerization inhibitor molecules, inspired by combretastatin A-4 (CA-4). CA-4 is a potent anticancer compound targeting tubulin polymerisation, however, poor pharmacokinetic profile and conversion from ‘cis’ to ‘trans’ configuration leads to a reduction in potency of the molecule. Inspired from various reported derivatives of CA-4 with ethylene bridge rigidification, two heterocyclic moieties were introduced to the synthesised molecules; namely ‘isoxazoline’, and ‘triazole’. These moieties have reported to improve pharmacokinetic profile, and synergize the anticancer potential. Both rings joined by a methine linker, were introduced replacing ethylene bridge of CA-4, with varying substitutions at the ‘A’ and ‘B’ ring. The synthesised derivatives were found active against breast cancer (MDA-MB-231), and lung cancer cell lines (A-549), with selective inhibition being specific to G2/M phase of the cell cycle. All the molecules showed significant cytotoxic potential from 0.49 µM-3.17 µM with 2f-6 displayed the IC50 value 0.401 ± 0.01 µM for A-549 -lung cancer cell line and 0.498 ± 0.03 µM for MDA-MB-231-breast cancer cell line. The cell cycle analysis, flow cytometry, and few other biological assays, supported the target specificity of molecules towards tubulin, and further immunohistochemistry analysis confirmed the anti-tubulin activity. The compound 2f-6, 5f-5, and 1f-6 were found to be the most potent inhibitors. The tubulin polymerization inhibition was confirmed with western blot analysis using tubulin antibody. The binding patterns of the molecules at the colchicine binding site (CBS) were analysed by molecular docking studies, which revealed that triazole ring portion of the molecules showed a tendency to mimic favourably as A-ring of CA-4. The Molecular Dynamic simulations were run on 2f-6, and 5f-5, which verified the authenticity and confirmed the stability of obtained binding poses from the docking results.

Keywords: Tubulin, Combretastatin A-4, 1,2,3-Triazole, Click Chemistry, Isoxazoline, Molecular Modelling, anticancer, Colchicine Binding Site (CBS)

Suggested Citation

Sharma, Akanksha and Yadav, Umesh Prasad and Singh, Sandeep and Holla, Harish, Design and Synthesis of New Tubulin Polymerization Inhibitors Inspired from Combretastatin A-4 (February 8, 2020). Proceedings of International Conference on Drug Discovery (ICDD) 2020, Available at SSRN: https://ssrn.com/abstract=3534755

Akanksha Sharma (Contact Author)

Central University of Karnataka ( email )

2nd Floor, Karya Soudha
Gulbarga University Campus
Gulbarga, Karnataka 585 106
India

Umesh Prasad Yadav

Central University of Punjab

Punjab
India

Sandeep Singh

Central University of Punjab

Punjab
India

Harish Holla

Central University of Karnataka

2nd Floor, Karya Soudha
Gulbarga University Campus
Gulbarga, Karnataka 585 106
India

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