Back to Search Start Over

N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia

Authors :
Taisa Regina Stumpf
Leandro F. Nascimento
Wanessa F. Altei
Andreas Vogt
Carolina Pereira de Souza Melo
Adriano D. Andricopulo
Marisa Jádna Silva Frederico
Alessandra Mascarello
Hikmat N. Daghestani
Adair R.S. Santos
Lívia B. Salum
Paulo César Leal
André B. Silveira
Angelo Brunelli Albertoni Laranjeira
Rafael Renatino Canevarolo
Louise Domeneghini Chiaradia-Delatorre
Patrícia D. Neuenfeldt
Rosendo A. Yunes
Billy W. Day
Laura L. Vollmer
Ricardo José Nunes
José Andrés Yunes
Source :
European journal of medicinal chemistry. 96
Publication Year :
2014

Abstract

Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg.

Details

ISSN :
17683254
Volume :
96
Database :
OpenAIRE
Journal :
European journal of medicinal chemistry
Accession number :
edsair.doi.dedup.....65570ed8efb502411bb0861cb21c04b4