Fujimoto Yuri, Mizuno Kanako, Nakamura Yuta, Arai Masayoshi, Kotoku Naoyuki
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu 525-8577, Shiga, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita 565-0871, Osaka, Japan.
Mar Drugs. 2025 Apr 20;23(4):179. doi: 10.3390/md23040179.
Simplified analogs of cortistatin A were synthesized and biologically evaluated to develop novel antitumor substances that target angiogenesis. To analyze the effect of substituents at positions corresponding to C-2 and/or C-4 of the A-ring, various pyrone- or pyridone-embedded analogs were designed and synthesized. Among the prepared analogs, the pyridone analog bearing a methyl group at C-2 and a hydroxyl group at C-4 showed potent and selective growth inhibitory activity against human umbilical vein endothelial cells (HUVECs, IC = 0.001 µM, selective index over that against human epidermoid carcinoma KB3-1 cells = 6400), exceeding those of natural products. The analog of oral administration exhibited excellent in vivo antitumor activity in mice subcutaneously inoculated with sarcoma S180 cells.
合成了可替他汀A的简化类似物并进行生物学评估，以开发靶向血管生成的新型抗肿瘤物质。为了分析A环中与C-2和/或C-4相对应位置的取代基的作用，设计并合成了各种嵌入吡喃酮或吡啶酮的类似物。在所制备的类似物中，在C-2处带有甲基且在C-4处带有羟基的吡啶酮类似物对人脐静脉内皮细胞显示出强效且选择性的生长抑制活性（HUVECs，IC = 0.001 μM，相对于对人表皮样癌KB3-1细胞的选择性指数 = 6400），超过了天然产物。口服给药的类似物在皮下接种肉瘤S180细胞的小鼠中表现出优异的体内抗肿瘤活性。
