| Summary: | In this study, celastrol (CEL) microbial transformation was performed by Streptomyces olivaceus CICC 23628 for the first time. Two new friedelanes derivatives (CEL-1 and CEL-2) as metabolites were isolated, and their structures were elucidated based on the NMR and HR-MS analysis. Then we investigated their anti-proliferation activities in three human cancer cell lines (A549, HCT-116, HepG2) in vitro. Mechanistic studies showed that CEL-2 could induce cell apoptosis and block cell-cycle on HCT-116 cells. The western blotting analysis showed that CEL-2 could suppress the STAT3′s phosphorylation as well as its downstream genes. Furthermore, SPR analysis revealed that CEL-2 could direct bind with STAT3 protein. These studies suggest that the derivative CEL-2 may exert an anti-colorectal cancer effect via inhibiting STAT3, thereby inducing apoptosis and blocking cell-cycle. Finally, we further verified the anti-tumor effect of CEL-2 on the colorectal cancer organoid model. Our researches suggest that the biotransformation of celastrol is a potential approach to discovering new STAT3 inhibitors as anti-tumor agent.
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