Total/Semi-Syntheses of Anticancer and Antifungal Natural Products and Drugs
Yogesh G. Shelke
Scientist, Medicinal Chemistry at Novo Nordisk, Boston, USA-02421
[email protected]
To serve biological functions, natural products are structurally and biologically optimized by evolution and thus play an important role in drug discovery. Nevertheless, the research in this area is hampered by several drawbacks associated with natural products, for example, poor pharmacological properties, toxicity, and limited availability. The total and semi-synthesis of those natural products and their derivatives is the most tractable option to eliminate these limitations. With this goal in mind, we have achieved the most efficient total/semi-syntheses of macrolide natural products, like epothilone B, halichondrin B, norhalichondrin B, eribulin, and amphotericin B. To improve the in-vivo stability and potency of epothilone B (anticancer natural product), various analogs were synthesized semi-synthetically, and the most potent derivative with potential application as payload for Antibody Drug Conjugates was discovered.1 In a separate study, a unified technique based on Nicholas etherification and radical cyclization is used to accomplish the shortest total syntheses of anticancer natural products/drugs such as halichondrin B,2 norhalichondrin B,3 and eribulin4. Amphotericin B is an exceptional antifungal drug; unfortunately, it is very toxic to the human kidney. With the help of extensive mechanistic investigation and biophysical experiments, the renal-sparing amphotericin B analog is developed, which has completed preclinical trials and currently is being tested in Phase 1 clinical trials.5 This talk will go into some of the specifics of the studies mentioned above.
References:
1) J. Org. Chem. 2020, 85, 2865–2917; 2) J. Am. Chem. Soc. 2021, 143, 9267– 9276; 3) J. Am. Chem. Soc. 2021, 143, 20970–20979; 4) Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2208938119; 5) Nature, 2023, 623, 1079–1085.