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Relevant academic research and scientific papers

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

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. [Figure not available: see fulltext.]

COMPLEX AND STRUCTURALLY DIVERSE COMPOUNDS

The invention provides a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of sp3 carbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.

A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products

High-throughput screening is the dominant method used to identify lead compounds in drug discovery. As such, the makeup of screening libraries largely dictates the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound-screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for the modulation of many drug targets. Here we describe a novel, general and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show through the evaluation of chemical properties (which include fraction of sp 3 carbons, ClogP and the number of stereogenic centres) that these compounds are significantly more complex and diverse than those in standard screening collections, and we give guidelines for the application of this strategy to any suitable natural product.