Geldanamycin, a Naturally Occurring Inhibitor of Hsp90 and a Lead Compound for Medicinal Chemistry

Kitson, Russell R. A.; Kitsonová, Dominika; Siegel, David; Ross, David; Moody, Christopher J.

Abstract

Geldanamycin remains a driver in the medicinal chemistry of heat shock protein 90 (Hsp90) inhibition, even half a century after its original isolation from nature. This Perspective focuses on the properties of the benzoquinone ring of the natural product that enable a range of functionalization reactions to take place. Therefore, inherent reactivity at C-17, where the methoxy group serves as a vinylogous ester, and at C-19 that demonstrates nucleophilic, enamide-type character toward electrophiles, and also as a conjugate acceptor to react with nucleophiles, has facilitated the synthesis of semisynthetic derivatives. Thus, a range of C-17-substituted amine derivatives has been investigated in oncology applications, with a number of compounds in this series reaching clinical trials. In contrast, the 19-position of geldanamycin has received less attention, although 19-substituted derivatives offer promise with markedly reduced toxicity compared to geldanamycin itself, while retaining Hsp90 inhibitory activity albeit with diminished potency in cellular studies.

Citation

Kitson, R. R. A., Kitsonová, D., Siegel, D., Ross, D., & Moody, C. J. (2024). Geldanamycin, a Naturally Occurring Inhibitor of Hsp90 and a Lead Compound for Medicinal Chemistry. Journal of Medicinal Chemistry, 67(20), 17946–17963. https://doi.org/10.1021/acs.jmedchem.4c01048

• Journal Article Type: Article
• Acceptance Date: Sep 20, 2024
• Online Publication Date: Oct 3, 2024
• Publication Date: Oct 24, 2024
• Deposit Date: Nov 11, 2024
• Publicly Available Date: Nov 11, 2024
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 67
• Issue: 20
• Pages: 17946–17963
• DOI: https://doi.org/10.1021/acs.jmedchem.4c01048
• Public URL: https://nottingham-repository.worktribe.com/output/40589746
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01048