Synthesis and antitumor activity of novel gibberellin derivatives with tetracyclic diterpenoid skeletons

Gibberellic acid (GA 3 ) is a tetracyclic diterpene compound which displays interesting bioactivities. Recently, its potential use for preparing antitumor drug leads has been highlighted, and various modification methods of GA 3 have been reported. Aiming at investigating GA 3 derivatives with potential antitumor activities, ring distortion of GA 3 under different conditions was carried out, and this was followed with amidation or substitution, yielding four series of derivatives. The chemical structure of these compounds were analyzed by 1 H-NMR, 13 C-NMR, HRMS, FTIR and polarimetry, and SXRD was employed to further confirm the spatial configurations of derivatives 3c and 7d . The antitumor activities of three series of derivatives were evaluated by using MTT assay and ELISA. Results shows that, among amide derivatives, compounds with a saturated linear amide showed better activity than those with an aromatic amide. Among ester derivatives, compounds with a meta -substituted benzyl group showed better activities than those with a para -substituted benzyl group. The antitumor activity of ester derivatives might possibly be linked with the inhibition of FGFR 1 activation and KDR activation. Overall, this study discussed how the antitumor activity of GA 3 was formed, thereby assisting the future design of more effective active GA 3 derivatives.