Shiozaki Masao, Tashiro Takuya, Koshino Hiroyuki, Shigeura Tomokuni, Watarai Hiroshi, Taniguchi Masaru, Mori Kenji
Laboratory for Immune Regulation, Research Center for Allergy and Immunology, RIKEN, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan.
Laboratory for Immune Regulation, Research Center for Allergy and Immunology, RIKEN, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan.
Bioorg Med Chem. 2014 Jan 15;22(2):827-33. doi: 10.1016/j.bmc.2013.12.009. Epub 2013 Dec 11.
RCAI-147 is one of the hydroxylated analogues of KRN7000 which is known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) and releases both T helper 1 (Th1) cytokines such as IFN-γ and T helper 2 (Th2) cytokines such as IL-4. KRN7000 has been anticipated as an antitumor drug or an adjuvant for viral infection such as influenza, because of its strong secretion of IFN-γ. In an interesting twist, it has been obvious in our previous paper that RCAI-147 induces much more Th2 cytokines (IL-4) than Th1 cytokines (IFN-γ) from iNKT cells compared to KRN7000, and shows fairly good result in the experimental autoimmune encephalomyelitis (EAE) test. Therefore, synthesis of RCAI-172 (C6-OH epimer of RCAI-147) was attempted to examine the biological activity. As a result, RCAI-172 was synthesized and its biological activity biased to Th2 response largely compared to that of KRN7000. However, this level decreased to approximately 61% compared to that of RCAI-147. And the clinical score of RCAI-172 for EAE suppression was disappointing. There exist seven chiral centers in the aglycon part of RCAI-172, and even though the change of configuration is just one position (C6-OH), the effect on both Th1/Th2 response and EAE test is fairly large.
RCAI-147是KRN7000的羟基化类似物之一，KRN7000是一种已知的可激活CD1d介导的不变自然杀伤T细胞（iNKT细胞）的配体，可释放T辅助1（Th1）细胞因子如IFN-γ和T辅助2（Th2）细胞因子如IL-4。由于KRN7000能强烈分泌IFN-γ，它一直被预期作为一种抗肿瘤药物或用于流感等病毒感染的佐剂。有趣的是，在我们之前的论文中已经很明显，与KRN7000相比，RCAI-147从iNKT细胞诱导产生的Th2细胞因子（IL-4）比Th1细胞因子（IFN-γ）多得多，并且在实验性自身免疫性脑脊髓炎（EAE）试验中显示出相当好的结果。因此，尝试合成RCAI-172（RCAI-147的C6-OH差向异构体）以研究其生物活性。结果，RCAI-172被合成出来，并且其生物活性与KRN7000相比在很大程度上偏向Th2反应。然而，与RCAI-147相比，这个水平下降到了大约61%。而且RCAI-172在抑制EAE方面的临床评分令人失望。RCAI-172的苷元部分存在七个手性中心，尽管构型变化只是一个位置（C6-OH），但对Th1/Th2反应和EAE试验的影响都相当大。
