苯并咪唑类似物作为有效的缺氧诱导因子抑制剂：合成、生物评价和药物特性分析。
Benzimidazole analogs as potent hypoxia inducible factor inhibitors: synthesis, biological evaluation, and profiling drug-like properties.
机构信息
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A. Department of Pharmaceutical Sciences, School of Pharmacy, South College, Knoxville, TN, U.S.A.
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
出版信息
Anticancer Res. 2014 Aug;34(8):3891-904.
AIM
To develop potent HIF-1α inhibitors for potential treatment of cancer.
MATERIALS AND METHODS
Chemical synthesis, HIF-luciferase assay, cytotoxic assay, platelet aggregation assay, western blot analysis, quantitative real-time PCR, aqueous solubility, protein binding, metabolic stability, and metabolic pathways.
RESULTS
Thirteen novel benzimidazole analogs were synthesized. Compounds 3a and 3k showed the highest anti-HIF-1α activity. They are significantly more effective than YC-1 in the suppression of HIF-1α protein expression based on western blot assay. They show comparable potency in inhibition of cancer cell migration. They are less potent in the inhibition of platelet aggregation. 3k had the most favorable drug-like properties, including long half-life in human liver microsomes, medium protein binding level and reasonable aqueous solubility.
CONCLUSION
The potent anti-HIF-1α activity and favorable drug-like properties of compound 3k suggest that it may hold great potential as an adjuvant therapy for cancer treatment through repression of HIF-1α protein expression.
目的
开发有效的 HIF-1α 抑制剂，用于癌症的潜在治疗。
材料与方法
化学合成、HIF-荧光素酶测定、细胞毒性测定、血小板聚集测定、western blot 分析、实时定量 PCR、水溶解度、蛋白结合、代谢稳定性和代谢途径。
结果
合成了 13 种新型苯并咪唑类似物。化合物 3a 和 3k 表现出最高的抗 HIF-1α 活性。基于 western blot 分析，它们在抑制 HIF-1α 蛋白表达方面比 YC-1 更有效。它们在抑制癌细胞迁移方面具有相当的效力。它们在抑制血小板聚集方面的效力较低。3k 具有最有利的类药性特征，包括在人肝微粒体中的长半衰期、中等蛋白结合水平和合理的水溶解度。
结论
化合物 3k 具有有效的抗 HIF-1α 活性和有利的类药性特征，表明它可能通过抑制 HIF-1α 蛋白表达，作为癌症治疗的辅助疗法具有很大的潜力。
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