Isoprene Side-chain of SMTP is Essential for Soluble Epoxide Hydrolase Inhibition and Cellular Localization

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 a tricyclic 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.