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.

中文翻译：

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具有四环二萜骨架的新型赤霉素衍生物的合成及其抗肿瘤活性

赤霉素（GA ₃）是一种显示出有趣生物活性的四环二萜化合物。近来，已经突出了其在制备抗肿瘤药物前导中的潜在用途，并且已经报道了GA _3的各种修饰方法。为了研究具有潜在抗肿瘤活性的GA ₃衍生物，在不同条件下进行了GA _3的环畸变，然后进行酰胺化或取代，得到四个系列的衍生物。通过¹ H-NMR，¹³ C-NMR，HRMS，FTIR和旋光法分析了这些化合物的化学结构，并使用SXRD进一步证实了衍生物3c的空间构型。和7d。采用MTT法和ELISA法对三种衍生物的抗肿瘤活性进行了评价。结果表明，在酰胺衍生物中，具有饱和直链酰胺的化合物显示出比具有芳族酰胺的化合物更好的活性。在酯衍生物中，具有间取代苄基的化合物表现出比具有对取代苄基的化合物更好的活性。酯衍生物的抗肿瘤活性可能与抑制FGFR ₁活化和KDR活化有关。总体而言，本研究讨论了GA ₃的抗肿瘤活性是如何形成的，从而有助于将来设计更有效的活性GA ₃衍生物。