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.

长春花生物碱和紫杉烷等微管蛋白相互作用剂在癌症化疗中起着根本作用，使细胞微管（MT）成为少数经过验证的抗癌靶标之一。癌症对经典MT抑制剂的抵抗力促使开发出具有更高功效和更低毒性的新型分子。为了设计结构简单的MT组装抑制剂，我们合成了31个3,4,5-三甲氧基hydr和25个衍生物或类似物。对接模拟表明，代表N-酰基hydr可在微管蛋白的秋水仙碱结合域内采用适当的立体化学。这些化合物中的几种在纳摩尔浓度范围内显示出抗白血病作用。化合物在生化和细胞水平上抑制MT组装的能力证实了对MT聚合的干扰。用最有效的化合物，带有1-萘基的3,4,5-三甲氧基-进行的选择性毒性研究表明，与受刺激的正常淋巴细胞相比，对白血病细胞具有显着的选择性毒性，并且在体内没有急性毒性。最后，在人急性淋巴细胞白血病鼠模型中，该分子的活性与长春新碱相同，每周剂量为1 mg / kg。