Title:Synthesis, Pharmacological Evaluation and Docking Study of a New Modulator of Microtubule Polymerization
VOLUME: 15 ISSUE: 7
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*
Affiliation:Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitaria, Rio de Janeiro-RJ, Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitaria, Rio de Janeiro-RJ, Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitaria, Rio de Janeiro-RJ, Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitaria, Rio de Janeiro-RJ, Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitaria, Rio de Janeiro-RJ, Laboratorio de Oncologia Experimental (LOE)-Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM)- Universidade Federal do Ceara, Fortaleza-CE, Laboratorio de Oncologia Experimental (LOE)-Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM)- Universidade Federal do Ceara, Fortaleza-CE, Laboratorio de Oncologia Experimental (LOE)-Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM)- Universidade Federal do Ceara, Fortaleza-CE, Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitaria, Rio de Janeiro-RJ, Instituto Nacional de Ciencia e Tecnologia de Farmacos e Medicamentos (INCT-INOFAR), Laboratorio de Avaliacao e Sintese de Substancias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitaria, Rio de Janeiro-RJ
Keywords:Tubulin, cytotoxic activity, cancer, microtubule, CA4, docking study.
Abstract: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.
