title: Synthesis and biological activity of hydroxylated analogues of KRN7000 (α-galactosylceramide).
abstract: KRN7000 is one of the α-galactosylceramides, which has a 2-hexacosanoylamino-3,4-dihydroxyoctadecyl group. This compound, known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) which release both T helper 1 (Th1) cytokines such as IFNγ and Th2 cytokines such as IL-4, has been anticipated as an antitumor drug, because of its strong secretion of IFNγ. This time, we focused on the hydroxylated analogues of KRN7000 which could be thought of as increasing hydrophilicity and showing bias to Th2 cytokine (IL-4) secretion. Therefore, they may become the drugs for autoimmune diseases for the following reasons: (i) compound OCH, one of the α-galactosylceramide analogues with a shorter sphingosine chain than KRN7000, increases hydrophilicity relative to KRN7000; and (ii) OCH is known to induce much more Th2 cytokines (IL-4) than Th1 cytokines from iNKT cells compared to KRN7000. Naturally, OCH has become one of the candidate drugs for autoimmune diseases. The more hydroxylated derivatives of KRN7000 are anticipated to induce Th2 bias. Therefore, eight analogues with 1-4 excess hydroxyl groups on the lipid chain of KRN7000 were synthesized to examine if they behave in the same way as OCH. As a result, three out of eight compounds biased largely to IL-4 secretion, and their effectiveness for experimental autoimmune encephalomyelitis (EAE) was examined. It was recognized that two compounds (†)RCAI-147/-160 showed good suppression of EAE symptoms.
authors: Laboratory for Immune Regulation, Research Center for Allergy and Immunology, RIKEN, Wako-shi, Saitama, Japan. shiozaki@rcai.riken.jp
authors: Masao
authors: M
authors: Shiozaki
authors: Takuya
authors: T
authors: Tashiro
authors: Hiroyuki
authors: H
authors: Koshino
authors: Tomokuni
authors: T
authors: Shigeura
authors: Hiroshi
authors: H
authors: Watarai
authors: Masaru
authors: M
authors: Taniguchi
authors: Kenji
authors: K
authors: Mori
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D005260:Female; D005699:Galactosylceramides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006900:Hydroxylation; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D005699:Galactosylceramides; D015847:Interleukin-4; C103873:KRN 7000