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SAR Investigation and Discovery of Water-Soluble 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazoles as Potent Tubulin Polymerization Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-17 , DOI: 10.1021/acs.jmedchem.0c01345 Ying-Jie Cui 1 , Chao Liu 1 , Chen-Chen Ma 2 , Ya-Ting Ji 1 , Yi-Li Yao 1 , Long-Qian Tang 1 , Cheng-Mei Zhang 1 , Jing-De Wu 1 , Zhao-Peng Liu 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-17 , DOI: 10.1021/acs.jmedchem.0c01345 Ying-Jie Cui 1 , Chao Liu 1 , Chen-Chen Ma 2 , Ya-Ting Ji 1 , Yi-Li Yao 1 , Long-Qian Tang 1 , Cheng-Mei Zhang 1 , Jing-De Wu 1 , Zhao-Peng Liu 1
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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.
中文翻译：
SAR研究和发现水溶性的1-甲基-1,4-二氢茚并[1,2- c ]吡唑类化合物是有效的微管蛋白聚合抑制剂
以先前发现的1-甲基-1,4-二氢茚并[1,2 c ]吡唑衍生物LL01为先导，对苯酚的6位和7位和苯胺的3位进行了系统的结构修饰。茚并吡唑核用于研究SAR和改善水溶性。在设计的茚并吡唑ID01 - ID33中，鉴定出一系列有效的MTA。作为盐酸盐，ID09和ID33表现出优异的水溶性和良好的Log P并显示出对多种肿瘤细胞（包括那些抗紫杉醇耐药的肿瘤细胞）低的纳摩尔浓度。他们通过靶向秋水仙碱位点抑制微管蛋白聚合，破坏细胞微管网络，并促进HepG2细胞周期阻滞和细胞凋亡。在HepG2异种移植小鼠模型中，ID09和ID33以25 mg / kg的口服剂量有效抑制肿瘤生长。每隔一天静脉注射（iv）10 mg / kg，ID09将肿瘤生长抑制了68％，而没有明显的毒性。
更新日期：2020-12-10
中文翻译：
SAR研究和发现水溶性的1-甲基-1,4-二氢茚并[1,2- c ]吡唑类化合物是有效的微管蛋白聚合抑制剂
以先前发现的1-甲基-1,4-二氢茚并[1,2 c ]吡唑衍生物LL01为先导，对苯酚的6位和7位和苯胺的3位进行了系统的结构修饰。茚并吡唑核用于研究SAR和改善水溶性。在设计的茚并吡唑ID01 - ID33中，鉴定出一系列有效的MTA。作为盐酸盐，ID09和ID33表现出优异的水溶性和良好的Log P并显示出对多种肿瘤细胞（包括那些抗紫杉醇耐药的肿瘤细胞）低的纳摩尔浓度。他们通过靶向秋水仙碱位点抑制微管蛋白聚合，破坏细胞微管网络，并促进HepG2细胞周期阻滞和细胞凋亡。在HepG2异种移植小鼠模型中，ID09和ID33以25 mg / kg的口服剂量有效抑制肿瘤生长。每隔一天静脉注射（iv）10 mg / kg，ID09将肿瘤生长抑制了68％，而没有明显的毒性。
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