New bis-norditerpene by biotransformation of favelines from Cnidoscolus quercifolius using Umbelopsis isabellina as biocatalyst

Favelines, tricyclic benzylcycloheptene diterpenes predominantly found in Cnidoscolus quercifolius, have demonstrated significant cytotoxic activity against human cancer cell lines, including melanoma. In this study, we employed a combinatorial approach to screen microbial strains for biotransformation, focusing on regioselective oxidation of the cyclohexyl ring in the faveline core structure. This strategy, applied directly to the crude plant extract, enabled the rapid identification of Umbelopsis isabellina as the active strain. Subsequent preparative biotransformation yielded a novel bis-norditerpene, 14-hydroxy-isofavelol (3). The new compound exhibited moderate cytotoxic activity (IC₅₀ = 68.8 μM) against chemoresistant human melanoma A2058 cells, which are resistant to dacarbazine but sensitive to vemurafenib. Compound 3 enhanced the cytotoxic effect of vemurafenib, reducing its IC₅₀ from 24.8 to 9.63 μM. This work demonstrates the utility of microbial biotransformation for generating new bioactive natural product derivatives and highlights the potential of 14-hydroxy-isofavelol as a chemosensitizing agent in melanoma therapy.