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.

Datwyler Sealing Technologies CZ Ltd Polní 224 50401 Nový Bydžov Czech Republic

Department of Organic and Bioorganic Chemistry Charles University Faculty of Pharmacy in Hradec Králové Akademika Heyrovského 1203 50005 Hradec Králové Czech Republic

Department of Pharmaceutical Sciences University of Colorado Anschutz Medical Campus 12850 East Montview Boulevard Aurora Colorado 80045 United States

School of Chemistry University of Nottingham University Park Nottingham NG7 2RD U K

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