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Derivation of Rapamycin: Adventures in Natural Product Chemistry

Sedrani, Richard, Cottens, Sylvain, Schuler, Walter and Kallen, Jörg (2019) Derivation of Rapamycin: Adventures in Natural Product Chemistry. Chimia., 73 (7). pp. 581-590. ISSN 0009-4293


The macrolide rapamycin was first described as an antifungal agent in 1975. It attracted our interest in the early 90s based on its reported immunosuppressive activity in transplantation models and based on indications that its mechanism of action was different from those of the known immunosuppressive agents ciclosporin and FK506, although the biological target and the molecular details were yet to be discovered. In this review we describe our efforts to chemically modify this complex and chemically very sensitive natural product. Despite the limitations regarding the reaction conditions compatible with rapamycin we discovered ways of selectively modifying specific functional groups. This allowed us, among others, to improve the stability of the parent molecule towards ring-opening. Our efforts culminated in the discovery and development of the 40-O-alkylated derivative everolimus which became a useful drug in solid organ transplantation, in various cancer indications and as the active principle of the market leading drug-eluting stent.

Item Type: Article
Date Deposited: 15 Oct 2019 00:45
Last Modified: 15 Oct 2019 00:45