Synthesis and Immunosuppressive Activity of 2-Substituted 2-Aminopropane-1,3-diols and 2-Aminoethanols

Abstract

A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)-hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.

FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells

“…T he FTY720 is a synthetic sphingosine analog (2-amino-(2-(2-(4-octophenyl) ethyl)-1,3-propanediol hydrochloride) of myriocin (1)(2)(3)(4). Currently, the discussion about its mode of action is mainly focused on its property to cause lymph node homing or sequestration of T cells.…”

“…In this scenario, FTY720 activates sphingosine-1-phosphate (S1P) 4 receptors and modulates migration after being effectively phosphorylated in vivo by sphingosine kinase 2 (SphK2) (5,6). FTY720-phosphate (FTY720-P) exhibits a potency comparable to S1P itself as an agonist at four of the five known G-protein-coupled S1PRs (S1P 1,3,4,5 ). Interference of FTY720 with S1P signaling hampers entry of lymphocytes into efferent lymphatics within lymph nodes, thereby delaying their subsequent return into circulation (7,8).…”

Sphingosine 1-phosphate chemical biology

“…Unlike myriocin, FTY720 does not inhibit SPT. FTY720 prolongs skin allografts in mice while evoking a profound lymphocytopenia [24]. We know now that this hematologic abnormality is a biologic signature of S1P1 receptor agonist drugs.…”

“…2, FTY720 can be conceptualized as consisting of a 'warhead', 'linker', and 'tail' regions. The head region is largely constrained by the requirements of SPHK2; that is, only one spatial arrangement around the amino carbon is allowed (this center is pro-chiral in FTY720, SPHK2 yields S-FTY720-P [54]) and only small alkyl substitutions are permitted at the amino carbon [24]. However, lack of an alkyl substitution at the amino carbon results in compounds that are too rapidly dephosphorylated in vivo (our unpublished data).…”

“…Myriocin, which is a fungal-derived phytosphingosine analog with a connection to Chinese herbal medicine [23], is an inhibitor of serine palmitoyl CoA transferase (SPT, the first enzyme in sphingolipid biosynthesis). Initially studied as a potential anti-fungal drug, myriocin was found to be an immunosuppressant in mice [24]. The impetus for FTY720 discovery was a need to avoid the gastrointestinal toxicity of myriocin and to eliminate the chiral centers in that densely functionalized lead compound.…”