Synthesis, conformation, and immunosuppressive activity of cyclosporines that contain epsilon-oxygen (4R)-4-[(E)-butenyl]-4,N-dimethyl-L-threonine analogues in the 1-position.
A series of CsA analogues that contain novel epsilon-oxygen isosteres of (4R)-4-[(E)-butenyl]-4,N-dimethyl-L-threonine (MeBmt) in the 1-position were synthesized. The key steps for the syntheses of enantiomerically pure epsilon-oxygen MeBmt analogues 4-7 were based on the stereoselective epoxidation of cis-allylic alcohol derivative 12 with a peracid, followed by the application of a base-catalyzed intramolecular rearrangement of epoxyurethane 15, which was derived from the reaction of epoxy alcohol 14 and methyl isocyanate. All epsilon-oxygen MeBmt analogues have the same stereochemistry and the same functional groups as those on the alpha,beta,gamma-carbons of MeBmt except for the double bond of MeBmt, which is replaced by the -OCH2-group. The syntheses of the peptide portion of CsA analogues followed the strategy we reported previously. The immunosuppressive activities of CsA analogues 28a-e, determined by inhibition of concanavalin A stimulated thymocytes, showed that 28b, which has the closest structural resemblance to MeBmt, retains about 7-10% of activity of CsA, whereas the analogues 28a, 28c, and 28e retain about 2-5% activity. It is interesting to note that 28d, which has the larger benzyl group on the end of the side chain, is about 20-25% as active as CsA. Extensive conformational analyses by 1D and 2D NMR indicated that the conformation of the 33-membered peptide ring system for all CsA analogues was very similar to that of CsA. However, the NMR analyses revealed that the 1-position side chain of all these CsA analogues adopted a novel conformation in chloroform by forming a different intramolecular hydrogen bond between the beta-OH and the epsilon-oxygen of the same residue. The NMR data also suggest that the chloroform conformation of these CsA analogues is similar to the conformation observed in the crystal structure of CsA in that the 1-position side chain is folded across the cyclic peptide ring system.
Sun
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University of Wisconsin, School of Pharmacy, Madison 53706.
Guillaume
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Dunlap
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Rich
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D055598:Chemical Phenomena; D002621:Chemistry; D003208:Concanavalin A / Q000037:antagonists & inhibitors; D003524:Cyclosporins / Q000138:chemical synthesis* / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D003208:Concanavalin A