Design, Synthesis, and Hypoxia-Inducible Factor-1α Inhibitory Activity Evaluation of Panaxadiol Derivatives Containing a Thiazole Moiety

The hypoxia-inducible factor-1 alpha (HIF-1 alpha) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Thiazole derivatives have been reported to have diverse biological activities, especially in terms of anti-tumor. Consequently, we hypothesized that the introduction of a thiazole functional group in PD was likely to improve the biological potency. Here, three series of PD derivatives containing a thiazole moiety were synthesized, including (a) sulfonyl-containing thiazole derivatives (5a-l), (b) urea-containing thiazole derivatives (7a-i), and (c) thiourea-containing thiazole derivatives (9a-i), and evaluated for HIF-1 alpha inhibitory activity using a Hep3B cell-based luciferase reporter assay. The results showed that about 1/3 of the target compounds showed moderate or strong HIF-1 alpha inhibitory activity, among which compounds 5d and 7b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42 mu M, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1 alpha protein in Hep3B cells at a concentration of 50 mu M. Molecular docking experiments were also performed to investigate the structure-activity relationship. Compounds 5d and 7b can be used as leads for further study and development of novel antitumor drugs.