519002-55-2

Upstream product

• 519002-93-8 (E)-(2R,3R,4S)-3-hydroxy-2,4-dimethyl-oct-6-en-1-oyl-L-valine-L-phenylalanine-hexahydropyridazine-3S-carboxylic acid methyl ester 
• 519002-34-7 (E)-(2R,3R,4S)-3-hydroxy-2,4-dimethyl-oct-6-enoic acid 
• 247186-16-9 (tert-butoxycarbonyl)-L-valine-L-phenylalanine-hexahydropyridazine-3S-carboxylic asid methyl ester 
• 69739-34-0 t-butyldimethylsiyl triflate 

Relevant academic research and scientific papers

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 (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.