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  • Title: N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia.
    Author: Salum LB, Mascarello A, Canevarolo RR, Altei WF, Laranjeira AB, Neuenfeldt PD, Stumpf TR, Chiaradia-Delatorre LD, Vollmer LL, Daghestani HN, de Souza Melo CP, Silveira AB, Leal PC, Frederico MJ, do Nascimento LF, Santos AR, Andricopulo AD, Day BW, Yunes RA, Vogt A, Yunes JA, Nunes RJ.
    Journal: Eur J Med Chem; 2015; 96():504-18. PubMed ID: 25951294.
    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.
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