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

Abstract

Gibberellic acid (GA3) 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 GA3 have been reported. Aiming at investigating GA3 derivatives with potential antitumor activities, ring distortion of GA3 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 1H-NMR, 13C-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 FGFR1 activation and KDR activation. Overall, this study discussed how the antitumor activity of GA3 was formed, thereby assisting the future design of more effective active GA3 derivatives.