Derivation of Rapamycin: Adventures in Natural Product Chemistry.

The macrolide rapamycin ( 1 ) was first described as an antifungal agent in 1975. Even though its biological target and the molecular details were yet to be discovered, rapamycin attracted our interest in the early 90s based on its reported immunosuppressive activity in transplantation models and based on findings that its mechanism of action was different from those of the known immunosuppressive agents ciclosporin and FK506. 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 2 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.

Identification and X-ray co-crystal structure of a small-molecule activator of LFA-1-ICAM-1 binding.

Stabilization of protein-protein interactions by small molecules is a concept with few examples reported to date. Herein we describe the identification and X-ray co-crystal structure determination of IBE-667, an ICAM-1 binding enhancer for LFA-1. IBE-667 was designed based on the SAR information obtained from an on-bead screen of tagged one-bead one-compound combinatorial libraries by confocal nanoscanning and bead picking (CONA). Cellular assays demonstrate the activity of IBE-667 in promoting the binding of LFA-1 on activated immune cells to ICAM-1.

Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data.

Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC(50) = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C(26)=C(27) exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC(50) = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 A of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.