Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002, China.
Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002, China; Department of Pharmaceutical Analysis, Wuya College of Innovation, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
Eur J Med Chem. 2021 Aug 5;220:113474. doi: 10.1016/j.ejmech.2021.113474. Epub 2021 Apr 21.
Four series of hypoxia-inducible factor-1 alpha (HIF-1α) functioning derivatives stemming from modifications to the C-29 carboxyl group of celastrol were designed and synthesized, and their anticancer activities were evaluated. To address the structure and activity relationship of each derivative, extensive structural changes were made. HRE luciferase reporter assay demonstrated that 12 modified compounds showed superior HIF-1α inhibitory activity. Among them, compound C6 exhibited the best features: firstly, the strongest HIF-1α inhibitory activity (IC = 0.05 μM, 5-fold higher than that of celastrol); secondly, lower cytotoxicity (22-fold lower, C6-16.85 μM vs celastrol-0.76 μM). Thus, the safety factor of C6 was about 112 times higher than that of celastrol. Western blot assay indicated that C6 may inhibit the expression of HIF-1α protein in cells. Additionally, C6 hindered tumor cell cloning, migration and induced cell apoptosis. It is worth mentioning that in the mouse tumor xenograft model, C6 (10 mg/kg) displayed good antitumor activity in vivo, showing a better inhibition rate (74.03%) than the reference compound 5-fluorouracil (inhibition rate, 59.58%). However, the celastrol treatment group experienced collective death after four doses of the drug. Moreover, C6 minimally affected the mouse weight, indicating that its application in vivo has little toxic effect. H&E staining experiments show that it could also exacerbate the degree of tumor cell damage. The results of water solubility experiment show that the solubility of C6 is increased by 1.36 times than that of celastrol. In conclusion, C6 is a promising antitumor agent through HIF-1α pathway.
设计并合成了源于雷公藤红素 C-29 羧基修饰的四个系列缺氧诱导因子-1α（HIF-1α）功能衍生物，并评价了它们的抗癌活性。为了研究每个衍生物的结构与活性关系，我们进行了广泛的结构修饰。HRE 荧光素酶报告基因检测显示，12 种修饰化合物表现出优异的 HIF-1α 抑制活性。其中，化合物 C6 表现出最佳特性：首先，对 HIF-1α 具有最强的抑制活性（IC=0.05 μM，比雷公藤红素高 5 倍）；其次，细胞毒性更低（22 倍，C6-16.85 μM 比 celastrol-0.76 μM）。因此，C6 的安全性系数比 celastrol 高约 112 倍。Western blot 实验表明，C6 可能通过抑制细胞中 HIF-1α 蛋白的表达来发挥作用。此外，C6 抑制肿瘤细胞克隆、迁移并诱导细胞凋亡。值得注意的是，在小鼠肿瘤异种移植模型中，C6（10mg/kg）在体内显示出良好的抗肿瘤活性，抑制率（74.03%）优于参比化合物 5-氟尿嘧啶（抑制率，59.58%）。然而，celastrol 治疗组在四剂药物后出现集体死亡。此外，C6 对小鼠体重的影响较小，表明其在体内应用的毒性较小。H&E 染色实验表明，它还可以加重肿瘤细胞损伤的程度。水溶性实验结果表明，C6 的溶解度比 celastrol 提高了 1.36 倍。总之，C6 通过 HIF-1α 通路是一种很有前途的抗肿瘤药物。
