Ideas about probing chemical space of natural products have engendered powerful strategies for creating unique and complex molecular architectures. Diterpenoids represent an important class of natural products that inspire new methodologies in synthetic chemistry due to their significance in biomedicines and biomaterials. Oridonin is a complex ent-kaurane diterpenoid that is featured with densely functionalized, stereochemistry-rich frameworks. To explore new synthetic approaches to access structurally diversified diterpenoids, our chemistry group initiated efforts to develop convergent, stereocontrolled synthesis of unique diterpenoids with the aid of NMR, mass spectrometry and X-ray techniques. Herein, we report the rational design, expeditious synthesis and biological activities of various diterpenoids towards valuable tools for identifying new drug targets in biomedical research and drug discovery existing outside the repertoire of compounds found in nature. Efficient synthetic approaches to the constructions of novel scaffolds around the A-ring of the oridonin template have been well established in our lab to readily access a structurally diverse library of diterpenoids. More importantly, a good number of these natural product-like molecules have demonstrated superior anticancer effects against various aggressive and drug-resistant human cancers (e.g. triple-negative breast cancer) in vitro and in vivo, as well as markedly improved drug-like properties, while some of them exhibit promising profiles as potent antiinflammatory agents. Several new analogues have been identified to inhibit Krüppel-like factor 5 (KLF5), a family member of zinc-finger-containing transcription factors which are involved in regulating expression of a wide range of genes, thereby affecting diverse cellular functions. Our research efforts in the chemical biology program open new avenues in identification of novel targets and discovery of potential therapeutic agents for cancer and inflammation.

Probing chemical space of oridonin-inspired diterpenoids to identify biologically important molecules

251st National Meeting (2016)

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