Otake Shinya, Ogawa Norihiro, Kitano Yoshikazu, Hasumi Keiji, Suzuki Eriko
Nat Prod Commun. 2016 Feb;11(2):223-7.
SMTPs, a family of natural small molecules that effectively treat ischemic stroke, are subject to clinical development. SMTPs enhance plasminogen activation and inhibit soluble epoxide hydrolase (sEH), leading to promotion of endogenous thrombolysis and anti-inflammation. The SMTP molecule consists of atricyclic γ-lactam moiety, an isoprene side-chain, and an N-linked side-chain. Here, we investigate the yet-to-be-characterized function of the isoprene side- chain of SMTPs in sEH inhibition and cellular distribution. The results demonstrated that oxidative modification as well as truncation of the side-chain abolished epoxide hydrolase inhibition. The introduction of a terminal hydroxy group exceptionally unaffected epoxide hydrolase, but led to impaired cellular localization, resulting in diminution of cellular epoxide hydrolase inhibition. Thus, the isoprene side-chain of SMTP is an important pharmacophore for epoxide hydrolase inhibition and cellular localization.
SMTPs是一类可有效治疗缺血性中风的天然小分子，目前正处于临床开发阶段。SMTPs可增强纤溶酶原激活并抑制可溶性环氧化物水解酶（sEH），从而促进内源性溶栓和抗炎作用。SMTP分子由一个三环γ-内酰胺部分、一个异戊二烯侧链和一个N-连接侧链组成。在此，我们研究了SMTPs异戊二烯侧链在抑制sEH和细胞分布方面尚未明确的功能。结果表明，侧链的氧化修饰以及截断均消除了对环氧化物水解酶的抑制作用。引入末端羟基对环氧化物水解酶的抑制作用没有影响，但导致细胞定位受损，从而降低了细胞对环氧化物水解酶的抑制作用。因此，SMTP的异戊二烯侧链是抑制环氧化物水解酶和细胞定位的重要药效基团。
