Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate.
A practical asymmetric synthesis of both enantiomers of the immunosuppressive FTY720-phosphate (2) was accomplished, and the enantiomers were pharmacologically evaluated. Several lipases showed considerable activity and enantioselectivity for O-acylation of N-acetyl FTY720 (3) or N-benzyloxycarbonyl FTY720 (7) in combination with vinyl acetate or benzyl vinyl carbonate as the acyl donors. The synthesis using the lipase-catalyzed acylation as the key step produced the enantiomerically pure (>99.5% ee) enantiomers of 2 in multigram quantities. (S)-Isomer of 2 had more potent binding affinities to S1P(1,3,4,5) and inhibitory activity on lymphocyte migration toward S1P than (R)-2, suggesting that (S)-isomer of 2 is responsible for the immunosuppressive activity after administration of 1. Severe bradycardia was observed in anesthetized rats when (S)-2 was administered intravenously, while (R)-2 had no clear effect on heart rate up to 0.3 mg/kg.
Kiuchi
Masatoshi
M
Research Laboratory III (Immunology), Mitsubishi Pharma Corporation, Kamoshida-cho 1000, Aoba-ku, Yokohama 227-0033, Japan. kiuchi.masatoshi@ms.m-pharma.co.jp
Adachi
Kunitomo
K
Tomatsu
Ayumi
A
Chino
Masao
M
Takeda
Shuzo
S
Tanaka
Yoshihito
Y
Maeda
Yasuhiro
Y
Sato
Noriko
N
Mitsutomi
Naoko
N
Sugahara
Kunio
K
Chiba
Kenji
K
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D011409:Propylene Glycols / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives; D013237:Stereoisomerism
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine