Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 2; pp. 425 - 432
• Main Authors: Kiuchi, Masatoshi, Adachi, Kunitomo, Tomatsu, Ayumi, Chino, Masao, Takeda, Shuzo, Tanaka, Yoshihito, Maeda, Yasuhiro, Sato, Noriko, Mitsutomi, Naoko, Sugahara, Kunio, Chiba, Kenji
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 17.01.2005; Elsevier Science
• Subjects: Animals; Asymmetric synthesis; Biological and medical sciences; Cell Line; Cell Movement - drug effects; Fingolimod Hydrochloride; Humans; Immunomodulators; Immunosuppressant; Immunosuppressive Agents - chemical synthesis; Immunosuppressive Agents - metabolism; Immunosuppressive Agents - pharmacology; Lipase; Lymphocytes - drug effects; Medical sciences; Mice; Models, Chemical; Molecular Structure; Pharmacology. Drug treatments; Propylene Glycols - chemical synthesis; Propylene Glycols - metabolism; Propylene Glycols - pharmacology; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid - metabolism; Sphingosine - analogs & derivatives; Sphingosine-1-phosphate; Stereoisomerism; Immunosuppressant; Asymmetric synthesis; Lipase; Sphingosine-1-phosphate; Rat; Arrhythmia; Enzyme; Toxicity; Rodentia; Triacylglycerol lipase; Cardiovascular disease; Esterases; Biological activity; Carboxylic ester hydrolases; Vertebrata; Bradycardia; Mammalia; Animal; Organic phosphate; Hydrolases; S configuration; Immunosuppressive agent; Lymphocyte; Enzymatic reaction; Biological receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.10.008

[Display omitted] 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.