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

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.

Automated summary

Four derivatives of hypoxia-inducible factor-1 alpha (HIF-1 alpha), with modifications to the C-29 carboxyl group of celastrol, were synthesized and evaluated for their anticancer activities. Among the derivatives, compound C6 showed the best features, exhibiting strong HIF-1 alpha inhibitory activity, low cytotoxicity, and promising safety factor. In vivo experiments with C6 demonstrated good antitumor activity with minimal toxic effects, making it a promising agent for cancer treatment.