247186-18-1Relevant articles and documents
Sanglifehrin-cyclophilin interaction: Degradation work, synthetic macrocyclic analogues, x-ray crystal structure, and binding data
Sedrani, Richard,Kallen, Joerg,Martin Cabrejas, Luisa M.,Papageorgiou, Charles D.,Senia, Francesco,Rohrbach, Stefan,Wagner, Dieter,Thai, Binh,Jutzi Eme, Anne-Marie,France, Julien,Oberer, Lukas,Rihs, Grety,Zenke, Gerhard,Wagner, Juergen
, p. 3849 - 3859 (2007/10/03)
Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC50 = 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 C26 = C27 exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC50 = 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.
Macrolide analogues of the novel immunosuppressant sanglifehrin: New application of the ring-closing metathesis reaction
Martin Cabrejas, Luisa M.,Rohrbach, Stefan,Wagner, Dieter,Kallen, Joerg,Zenke, Gerhard,Wagner, Juergen
, p. 2443 - 2446 (2007/10/03)
Macrocycles containing a conjugated 1,3-diene moiety have been synthesized for the first time in good yields by the ring-closing metathesis reaction [Eq. (1)]. The new compounds represent cyclophilin-binding, simplified analogues of the macrocyclic core of sanglifehrin A, an immunosuppressant which binds with high affinity to cyclophilin.
