AI Article Synopsis
- - Researchers modified a compound called LL01 to improve its water solubility and explored its structure-activity relationships (SARs) by making changes to specific positions on the chemical structure.
- - The modified compounds were found to be potent microtubule-targeting agents (MTAs) that effectively inhibited tumor cell growth, including drug-resistant types, by disrupting microtubule networks and inducing cell death.
- - In animal studies, these new compounds significantly reduced tumor growth in mice at relatively low dosages, with one method showing a 68% suppression rate without causing noticeable toxicity.
Article Abstract
Taking the previously discovered 1-methyl-1,4-dihydroindeno[1,2]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 -, a series of potent MTAs were identified. As the hydrochloride salt(s), and showed excellent aqueous solubility and favorable Log 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, and 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, suppressed tumor growth by 68% without obvious toxicity.
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| http://dx.doi.org/10.1021/acs.jmedchem.0c01345 | DOI Listing |
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