SAR Investigation and Discovery of Water-Soluble 1-Methyl-1,4-dihydroindeno[1,2- c]pyrazoles as Potent Tubulin Polymerization Inhibitors

Abstract

Taking the previously discovered 1-methyl-1,4-dihydroindeno[1,2c]pyrazol derivative LL01 as a lead, systematic structural modifications were made at the phenolic 6- and 7-positions and the aniline at the 3-position of the indenopyrazole core to investigate the SARs and to improve water solubility. Among the designed indenopyrazoles ID01-ID33, a series of potent MTAs were identified. As the hydrochloride salt(s), ID09 and ID33 showed excellent aqueous solubility and favorable Log P value and displayed noteworthily low nanomolar potency against a variety of tumor cells, including those taxol-resistant ones. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted HepG2 cell cycle arrest and cell apoptosis. In the HepG2 xenograft mouse model, ID09 and ID33 effectively inhibited tumor growth at an oral dose of 25 mg/kg. At an intravenous (iv) injection dose of 10 mg/kg every other day, ID09 suppressed tumor growth by 68% without obvious toxicity.