Sanglifehrin B
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| Category | Enzyme inhibitors |
| Catalog number | BBF-02864 |
| CAS | |
| Molecular Weight | 1072.37 |
| Molecular Formula | C60H89N5O12 |
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Description
It is a cyclophilin combination produced by the strain of Streptomyces sp. A92-308110. The affinity of Sanglifehrin B to Cyclophilin is 10-20 times stronger than Cyclosporin A. The immunosuppressive effect of Sanglifehrin is lower than Cyclosporin A by mixed lymphocyte reaction assay.
Specification
| Synonyms | SFB |
| IUPAC Name | (3S,6S,9R,10R,11S,12S,13E,15E,18S,21S)-18-[(2E,4E,8S,9S)-10-[(2S,3R,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-4-en-2-yl]-9-hydroxy-8-methyldeca-2,4-dien-2-yl]-10,12-dihydroxy-3-[(3-hydroxyphenyl)methyl]-11-methyl-9-(3-oxobutyl)-6-propan-2-yl-19-oxa-1,4,7,25-tetrazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone |
| Canonical SMILES | CCC1CC(C2(C(=CC(C(O2)CC(C(C)CCC=CC=C(C)C3CC=CC=CC(C(C(C(C(=O)NC(C(=O)NC(C(=O)N4CCCC(N4)C(=O)O3)CC5=CC(=CC=C5)O)C(C)C)CCC(=O)C)O)C)O)O)C)C)NC1=O)C |
| InChI | InChI=1S/C60H89N5O12/c1-11-44-31-40(8)60(63-55(44)71)39(7)30-38(6)52(77-60)34-50(69)36(4)20-14-12-15-21-37(5)51-26-17-13-16-25-49(68)42(10)54(70)46(28-27-41(9)66)56(72)62-53(35(2)3)57(73)61-48(33-43-22-18-23-45(67)32-43)58(74)65-29-19-24-47(64-65)59(75)76-51/h12-13,15-18,21-23,25,30,32,35-36,38,40,42,44,46-54,64,67-70H,11,14,19-20,24,26-29,31,33-34H2,1-10H3,(H,61,73)(H,62,72)(H,63,71)/b15-12+,17-13+,25-16+,37-21+/t36-,38+,40-,42-,44-,46+,47-,48-,49-,50-,51-,52-,53-,54+,60-/m0/s1 |
| InChI Key | LXZHHFFYSBIHSF-ODFZBKLOSA-N |
Properties
| Appearance | White Powder |
| Melting Point | 117-121°C |
| Solubility | Soluble in Methanol |
Reference Reading
1. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110. II. Structure elucidation, stereochemistry and physico-chemical properties
T Fehr, J Kallen, L Oberer, J J Sanglier, W Schilling J Antibiot (Tokyo). 1999 May;52(5):474-9. doi: 10.7164/antibiotics.52.474.
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.
2. Enantioselective Synthesis and Biological Evaluation of Sanglifehrin A and B and Analogs
Chia-Fu Chang, Hope A Flaxman, Christina M Woo Angew Chem Int Ed Engl. 2021 Jul 26;60(31):17045-17052. doi: 10.1002/anie.202103022. Epub 2021 Jun 24.
Sanglifehrin A and B are immunosuppressive macrocyclic natural products endowed with and differentiated by a unique spirocyclic lactam. Herein, we report an enantioselective total synthesis and biological evaluation of sanglifehrin A and B and analogs. Access to the spirocyclic lactam was achieved through convergent assembly of a key pyranone intermediate followed by a stereo-controlled spirocyclization. The 22-membered macrocyclic core was synthesized by ring-closing metathesis in the presence of 2,6-bis(trifluoromethyl) benzeneboronic acid (BFBB). The spirocyclic lactam and macrocycle fragments were united by a Stille coupling to furnish sanglifehrin A and B. Additional sanglifehrin B analogs with variation at the C40 position were additionally prepared. Biological evaluation revealed that the 2-CF3 analog of sanglifehrin B exhibited higher anti-proliferative activity than the natural products sanglifehrin A and B in Jurkat cells. Both natural products induced higher-order homodimerization of cyclophilin A (CypA), but only sanglifehrin A promoted CypA complexation with inosine-5'-monophosphate dehydrogenase 2 (IMPDH2). The synthesis reported herein will enable further evaluation of the spirolactam and its contribution to sanglifehrin-dependent immunosuppressive activity.
3. Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family
Matthew A Gregory, Michael Bobardt, Susan Obeid, Udayan Chatterji, Nigel J Coates, Teresa Foster, Philippe Gallay, Pieter Leyssen, Steven J Moss, Johan Neyts, Mohammad Nur-e-Alam, Jan Paeshuyse, Mahmood Piraee, Dipen Suthar, Tony Warneck, Ming-Qiang Zhang, Barrie Wilkinson Antimicrob Agents Chemother. 2011 May;55(5):1975-81. doi: 10.1128/AAC.01627-10. Epub 2011 Mar 7.
Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
