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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthesis, Pharmacological Evaluation and Docking Study of a New Modulator of Microtubule Polymerization

Author(s): Teiliane R. Carneiro, Daniel N. do Amaral, Harold H. Fokoue, Carlos M.R. Sant`Anna, Maria L.G. Porras, Augusto C.A. Oliveira, Bruno C. Cavalcanti, Claudia Pessoa, Eliezer J. Barreiro and Lidia M. Lima*

Volume 15, Issue 7, 2018

Page: [778 - 786] Pages: 9

DOI: 10.2174/1570180814666171012162557

Price: $65


Objectives: The main goal of this paper was to conduct the synthesis to determine cytotoxic activity and to carry out docking studies on new LASSBio-1586 isosteres. LASSBio-1586 is a new combretastatin A4 (CA4) analogue previously identified as a simple antitumor drug candidate, able to inhibit microtubule polymerization with broad in vitro and in vivo cytotoxic activity.

Methods: The new isosteres (7b-7h, 8a and 9a) were evaluated against HL-60, OVCAR-8, HCT8 and LUCENA tumor cell lines, using cytotoxic test of MTT. The tubulin polymerization assay was performed using a tubulin polymerization assay kit from cytoskeleton® and by CEREP employing a single concentration of 10 µM. Binding mode at β-tubulin colchicine binding site was stablished by blind molecular docking studies.

Results: LASSBio-1920 (7h) was identified as the most potent cytotoxic compound with IC50 values ranging from 0.75 nM to 11.5 nM, although it was inactive against MDR tumor cell line LUCENA (IC50 = 80 µM). This compound presented remarkable cytotoxic selective index in comparison with CA4 and LASSBio-1586. Its ability to modulate microtubule polymerization was confirmed and its mode of interaction with colchicine binding site in β-tubulin was demonstrated.

Conclusion: Compound 7h is a new isostere of LASSBio-1586 that displayed potent cytotoxic activity and better cytotoxic selectivity index and has been shown to interact with DAMA-colchicine in its co-crystal with β-tubulin.

Keywords: Tubulin, cytotoxic activity, cancer, microtubule, CA4, docking study.

Graphical Abstract

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