Sanglifehrins A, B, C and D, Novel Cyclophilin-binding Compounds Isolated from Streptomyces sp. A92-308110. II. Structure Elucidation, Stereochemistry and Physico-chemical Properties.

Abstract

A novel class of macrolides, the sanglifehrins, was discovered by screening of actinomycete strains with a cyclophilin-binding assay. The chemical structures and absolute stereochemistries of the sanglifehrins A, B, C and D were determined unambiguously by NMR-techniques and by X-ray crystallography of the complex with cyclophilin A.Sanglifehrin A consists of a 22-membered macrocycle containing a tripeptide subunit and features in position 23 a chain of nine carbon atoms bearing a spirocyclic substituent. Sanglifehrins A and B are genuine metabolites whereas sanglifehrins C and D are artefacts.Screening for cyclophilin binding metabolites from actinomycete strains led to the discovery of a novel class of compounds, which were named sanglifehrins. The taxonomy, fermentation, isolation and biological activity are described in the foregoing paper1}.In this part we describe the structure elucidation mainly done by NMR-analysis, and give the chemical characteristics of these newmicrobial compounds.Methods Spectroscopy The XHand 13C NMRspectra of the sanglifehrins were recorded in T>MSO-d6 on a Bruker Avance DMX-500spectrometer with TMSas internal standard. The 1H, 13C and 15N NMRshifts are listed in Table 2 and image, at a crystal-to-detector distance of 130mm.Data processing was done with the programs DENZO1.5.ll &Scalepack2), and the CCP43.0-package3). The overall Rsymon intensities for a total of 179130 measurements of 41 552 independent reflections in the resolution range 15A-1.6A (completeness 99.2%) was 7.5%.The structure was solved by molecular replacement and refined with the program X-PLOR, Version 3.14).

Cutting Edge: Sanglifehrin A, a Novel Cyclophilin-Binding Immunosuppressant Blocks Bioactive IL-12 Production by Human Dendritic Cells

“…S anglifehrins, described originally by Sanglier et al (1,2), are novel immunophilin-binding immunosuppressants with an unknown mechanism of action that are produced by the actinomycetes strain Streptomyces A92-308110. The immunophilin-binding agent cyclosporin A (CsA) 3 binds to cyclophilin and inhibits activity of the calcineurin phosphatase, whereas both FK506 and rapamycin (Rapa) bind to the FK506 binding protein but inhibit two different effector proteins: calcineurin phosphatase and mammalian target of Rapa (mTOR), respectively (3,4).…”

Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells

“…These reports show that CypA might be important for tumorigenesis in solid tumors. CypA is also an immunophilin and a cytosolic receptor for the immunosuppressive drugs cyclosporin A (CsA) (5) and sanglifehrin A (SFA) (16). CsA binds to CypA, and this complex inhibits calcineurin, a calcium-dependent phosphatase, that regulates the expression of various cytokine genes ONCOLOGY REPORTS 23: 1053-1062, 2010 Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells (17).…”

Sanglifehrin A Blocks Key Dendritic Cell Functions In Vivo and Promotes Long-Term Allograft Survival Together with Low-Dose CsA

“…Sanglifehrins represent novel immunophilin-binding agents, that exhibit >10 times higher binding affinity to the intracellular receptor of CsA, cyclophilin A, but unlike the latter, do not inhibit calcineurin phosphatase activity (7)(8)(9)(10)(11). SFA has an unique chemical structure consisting of a 22-membered macrocycle containing a tripeptide subunit and features in position 23 a chain of nine carbon atoms bearing a spirocyclic substituent (8).…”

“…SFA has an unique chemical structure consisting of a 22-membered macrocycle containing a tripeptide subunit and features in position 23 a chain of nine carbon atoms bearing a spirocyclic substituent (8). In vitro experiments revealed that sanglifehrin A (SFA) has no effects on targets of known immunosuppressants (9).…”