The discovery of water-soluble indazole derivatives as potent microtubule polymerization inhibitors

Eur J Med Chem. 2023 Oct 18;262:115870. doi: 10.1016/j.ejmech.2023.115870. Online ahead of print.ABSTRACTTaking a previously discovered indazole derivative 1 as a lead, systematic structural modifications were performed with an indazole core at the 1- and 6-positions to improve its aqueous solubility. Among the designed indazole derivatives, 6-methylpyridin-3-yl indazole derivative 8l and 1H-indol-4-yl indazole derivative 8m exhibited high potency in the low nanomolar range against A549, Huh-7, and T24 cancer cells, including Taxol-resistant variant cells (A549/Tax). As a hydrochloride salt, 8l exhibited much improved aqueous solubility, and its log P value fell into a favorable range. In mechanistic studies, 8l impeded tubulin polymerization through interacting with the colchicine site, resulting in cell cycle arrest and cellular apoptosis. In addition, compared to lead compound 1, 8l reduced cell migration and led to more potent inhibition of tumor growth in vivo without apparent toxicity. In summary, indazole derivative 8l could work as a potential anticancer agent and deserves further investigation for cancer therapy.PMID:37890199 | DOI:10.1016/j.ejmech.2023.115870
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research