Synthesis and biological activity of hydroxylated analogues of KRN7000 (α-galactosylceramide).

Masao Shiozaki, Takuya Tashiro, Hiroyuki Koshino, Tomokuni Shigeura, Hiroshi Watarai, Masaru Taniguchi, Kenji Mori

Index: Carbohydr. Res. 370 , 46-66, (2013)

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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.Copyright © 2013 Elsevier Ltd. All rights reserved.