Design, synthesis of novel celastrol derivatives and study on their antitumor growth through HIF-1 alpha pathway

Shang Fan-Fan; Wang Jing Ying; Xu Qian; Deng Hao; Guo Hong-Yan; Jin Xuejun; Li Xiaoting; Shen Qing-Kun; Quan Zhe-Shan

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Design, synthesis of novel celastrol derivatives and study on their antitumor growth through HIF-1 alpha pathway

机译：通过HIF-1α通路设计，综合新型Celastrol衍生物及其抗肿瘤生长研究

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Four series of hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha inhibitory activity. Among them, compound C6 exhibited the best features: firstly, the strongest HIF-1 alpha inhibitory activity (IC50 = 0.05 mu M, 5-fold higher than that of celastrol); secondly, lower cytotoxicity (22-fold lower, C6-16.85 mu M vs celastrol-0.76 mu M). 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-1 alpha 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-1 alpha pathway. (C) 2021 Elsevier Masson SAS. All rights reserved.

机译：设计并合成了四个系列的缺氧诱导因子-1α（HIF-1α）功能衍生物，其来源于对雷公藤红素C-29羧基的修饰，并对其抗癌活性进行了评估。为了解决每个衍生物的结构和活性关系，进行了广泛的结构变化。HRE荧光素酶报告分析表明，12种修饰化合物显示出优越的HIF-1α抑制活性。其中，化合物C6表现出最好的特性：第一，最强的HIF-1α抑制活性（IC50=0.05μM，比雷公藤红素高5倍）；其次，细胞毒性较低（C6-16.85μM比celastrol-0.76μM低22倍）。因此，C6的安全系数大约是雷公藤红素的112倍。westernblot分析表明，C6可能抑制HIF-1α蛋白在细胞中的表达。此外，C6阻碍了肿瘤细胞的克隆、迁移和诱导细胞凋亡。值得一提的是，在小鼠异种移植瘤模型中，C6（10 mg/kg）显示出良好的体内抗肿瘤活性，显示出比参考化合物5-氟尿嘧啶（抑制率59.58%）更好的抑制率（74.03%）。然而，celastrol治疗组在服用四剂药物后集体死亡。此外，C6对小鼠体重的影响最小，表明其在体内的应用几乎没有毒性作用。H&E染色实验表明，它也可能加剧肿瘤细胞的损伤程度。水溶性实验结果表明，C6的溶解度比雷公藤红醇提高了1.36倍。综上所述，C6通过HIF-1α途径是一种很有前途的抗肿瘤药物。（c）2021爱思唯尔马松SAS。版权所有。

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来源
《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2021年第1期|共14页
作者
Shang Fan-Fan; Wang Jing Ying; Xu Qian; Deng Hao; Guo Hong-Yan; Jin Xuejun; Li Xiaoting; Shen Qing-Kun; Quan Zhe-Shan;
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作者单位

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

Yanbian Univ Coll Pharm Key Lab Nat Med Changbai Mt Minist Educ Yanji 133002 Peoples R China;

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原文格式 PDF
正文语种 eng
中图分类药学;
关键词
Celastrol; HIF-1 alpha; Antitumor; In vivo;

机译：雷公藤红素;HIF-1α;抗肿瘤;体内;

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Design, synthesis of novel celastrol derivatives and study on their antitumor growth through HIF-1 alpha pathway

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