Design, synthesis, and evaluations of the antiproliferative activity and aqueous solubility of novel carbazole sulfonamide derivatives as antitumor agents

Article

作者: Hu, Xinyue ; Sun, Lianqi ; Wang, Chenxi ; Jiang, Zhi ; Li, Zhuorong ; Wu, Yanbin ; Chen, Xiaofang ; Hu, Laixing

Optimization of IG-105 (1) on the carbazole ring provided five series of new carbazole sulfonamides derivatives, 7a-e, 8a-g, 9a-g, 10a-e, and 11a-g. All of the compounds were evaluated against HepG2, MCF-7, MIA PaCa-2, and Bel-7402 cells for antiproliferative activity. Each series of compounds was 2-5 times more active against HepG2 cells (IC₅₀: 1.00-10.0 μM) than the other three tumor cell lines. Several representative compounds, selected from each series, showed aqueous solubility (13.4-176.5 µg/mL at pH 7.4 and 2.0) better than 1, with the aqueous solubility of corresponding salts > 30 mg/mL. From the results of evaluating the effects of the compounds 7b, 8c, 9c, 10c and 11c on tubulin in vitro, we speculated that their targets were different from those of 1 and CA-4P. We tested the antitumor activity of the representative compound 7b·HCl (10 mg/kg) in an in vivo study and found that its tumor growth inhibition rate was 41.1%. The tumor growth inhibition rate of 7b·HCl (20 mg/kg) was 54.6%, whereas the tumor growth inhibition rate of CA-4P (50 mg/kg) was 48.3%. And in another batch of in vivo antitumor activity testing, 9c·HCl and 11c·HCl at doses of 10 mg/kg resulted in 61.1% and 50.0% inhibition, respectively. These promising results warrant further development of the derivatives, which may use a novel mechanism and show potential potency as antitumor drug candidates.

2019-02-01·Die Pharmazie4区 · 医学

Simplified LC-MS/MS method for quantification of IG-105, a novel tubulin ligand, and its application to the pharmacokinetic study in rats at the anticancer effective dose.

4区 · 医学

Article

作者: Li, C. R. ; Hu, X. X. ; Li, G. Q. ; Lu, X. ; Nie, T. Y. ; Zhao, R. ; Wang, X. K. ; Yang, X. Y. ; Pang, J. ; You, X. F.

IG-105, N-(2, 6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide, a novel carbazole sulfonamide, shows a potent anticancer activity in a variety of human tumor cells in vitro and in vivo. In the present study, a rapid and convenient liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and applied to the pharmacokinetic study of IG-105 in rats. Chromatographic separation was accomplished on a C₁₈ column using an isocratic mobile phase of acetonitrile-water-acetic acid (56:44:0.2, v/v/v). The ion transitions of IG-105 and combretastatin A4 (internal standard) in selected reaction monitoring mode were m/z 398→154 and m/z 317→286, respectively. The assay exhibited good linearity over the range of 2-512 ng/mL. Intra- and inter-day precisions were within 8.2 %, and the accuracies ranged from -6.0 to 3.7 %. The extraction recoveries were higher than 90 %, and the matrix effects were negligible. All quality control samples were stable at different storage conditions. The validated LC-MS/MS method was successfully applied to a preclinical pharmacokinetic study of IG-105 in rats after a single oral dose of 100, 250, or 1000 mg/kg which showed tumor growth inhibition activity. The absorption of IG-105 was proved to be rapid but saturated to a certain extent into the blood circulation, from where it was distributed and eliminated gradually.

2008-10-01·Clinical Cancer Research1区 · 医学

N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer

1区 · 医学

Article

作者: Jiang, Jian-Dong ; Boykin, David W. ; Kong, Wei-Jia ; Zhang, Sheng-Hua ; Shao, Rong-Guang ; Hu, Lai-Xing ; You, Xue-Fu ; He, Hong-Wei ; Wang, Yue-Ming ; Qu, Jing-Rong ; Zhang, Liang-Ren ; Li, Yan ; Li, Zhuo-Rong ; Peng, Zong-Gen ; Liu, Zhen-Ming

AbstractPurpose: We have synthesized a new tubulin ligand N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide (IG-105). This work investigates its anticancer effect and mechanism.Experimental Design: Anticancer efficacy was evaluated at the molecular target, cancer cells and nude mice. The mechanism was explored at submolecular, molecular, and cellular levels.Results: IG-105 showed a potent activity against human leukemia and solid tumors in breast, liver, prostate, lung, skin, colon, and pancreas with IC50 values between 0.012 and 0.298 μmol/L. It was also active in drug-resistant tumor cells and not a P-glycoprotein substrate. It inhibited microtubule assembly followed by M-phase arrest, Bcl-2 inactivation, and then apoptosis through caspase pathways. The colchicine pocket on tubulin is the binding site of IG-105. Nude mice experiments showed that IG-105 monotherapy at 100 mg/kg i.p. (q2d) yielded 81% inhibition of Bel-7402 hepatoma growth and at 275 mg/kg i.p. (q2d) completely inhibited the tumor growth. MCF-7 breast cancer in nude mice showed a similar therapeutic response to IG-105. Acute toxicity of IG-105 was not found even at 1,000 mg/kg i.p. In combination with oxaliplatin or doxorubicin, IG-105 converted each of these subcurative compounds into a curative treatment with complete inhibition for tumor growth in the hepatoma-bearing nude mice. The combination was more active than either drug. In no experiment was toxicity increased by combination chemotherapy.Conclusions: IG-105 inhibits microtubule assembly by binding at colchicine pocket. It shows a potent anticancer activity in vitro and in vivo and has good safety in mice. We consider IG-105 merits further investigation.

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	药物发现	中国	山西普德药业有限公司	-
肿瘤	药物发现	中国	Georgia State University	-
肿瘤	药物发现	中国	中国医学科学院医学生物技术研究所	-