Total Synthesis of FK 506 and an FKBP Probe Reagent, (C8, C9-13C2)-FK 506. Chemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands.

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  • ＦＫ５０６およびＦＫＢＰプローブ試薬，（Ｃ８，　Ｃ９‐｀１３´Ｃ２）‐ＦＫ５０６の全合成　イムノフィリンと，その免疫抑制剤リガンドの化学と生物学
  • FK506 オヨビ FKBP プローブ シヤク C8 C9-13C2 FK50
  • Chemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands
  • イムノフィリンと, その免疫抑制剤リガンドの化学と生物学

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Asymmetric syntheses of FK 506 and (C8, C9-13C2) -FK 506 are reported. The latter compound was designed to facilitate an investigation of the interactions between FK 506 and its receptor, the recently discovered immunophilin, FKBP. The synthesis involved the preparation of intermediates 7-9 in nonracemic forms. The key coupling reactions included a Cram-selective addition of the vinyl Grignard reagent derived from bromide 9 to aldehyde 8 and the addition of the lithioanion of phosphonamide 7 to aldehyde 43, followed by thermal elimination. Dithiane 44 was then hydrolyzed, and glycolic ester 6 (or 6*) was added via an aldol reaction that allowed the introduction of 13C labels at C8 and C9. Elaboration to FK 506 proceeded via a Mukaiyama lactamization reaction and a selective deprotection/oxidation sequence, the efficiency of which was critically dependent upon the order of protecting group removal.<BR>13C labeled FK 506 (2) -FKBP drug protein complex was examined by 13C NMR ; the experiments did not show an enzyme bound tetrahedral intermediate, but revealed a noncovalent, fully reversible interaction of the drug with its receptor.<BR>Also delineated are the recent researches aiming at understanding the structural basis for the molecular recognition of immunosuppressants by immunophilins and the biological consequences of their interactions.

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