The conversion of oridonin to spirolactone-type or enmein-type diterpenoid: Synthesis and biological evaluation of ent-6,7-seco-oridonin derivatives as novel potential anticancer agents

Starting from commercial available natural product oridonin (1), a practical synthesis of ent-6,7-seco-oridonin derivatives (2, 3, 5, and 9) was accomplished and their biological activities were evaluated. The conversion of spirolactone-type diterpenoid to enmein-type was first completed. The results demonstrated that all synthesized ent-6,7-seco-oridonin derivatives could markedly inhibit the proliferation of cancer cells. Compared with Taxol, the most cytotoxic compound 5 has similar potency in A549 cell and slightly less cytotoxicity in Bel-7402 cell. Compound 5 was also more potent than parent compound oridonin in mice with MGC-803 gastric cancer in vivo. Then a series of novel 14-O-derivatives of 5 were further designed and synthesized, which showed better activity than 5 and similar activity as Taxol in vitro. The structure–activity relationships of oridonin derivatives were also discussed in the present investigations. The conversion of oridonin to spirolactone-type or enmein-type diterpenoid were accomplished, and a series of 14-O-derivatives of ent-6,7-seco-oridonin were synthesized and evaluated as novel potential anticancer agents. [Display omitted] ► The synthesis of ent-6,7-seco-oridonin derivatives were accomplished and evaluated. ► Compound 5 showed stronger anticancer activity than oridonin in vitro and in vivo. ► A series of 14-O-derivatives of 5 with improved potency were designed and obtained. ► Some 14-O-derivatives of 5 showed similar cytotoxicity as Taxol in vitro. ► The structure–activity relationships of the derivatives of oridonin were concluded.