Triterpenoids with diverse skeletons from the roots of Rhus chinensis and their protective effects on isoproterenol-induced heart failure in zebrafish

Abstract

In the ongoing quest to discover previously unreported lead compounds that provide protection against heart failure (HF), ten formerly undescribed (1–10) and nine known (11–19) triterpenoids were obtained from the roots of Rhus chinensis Mill. The isolated triterpenoids exhibited distinct skeletal types, including rare 17-epi-dammarane (1, 6, 7, 11, and 12), conventional dammarane (2–5, 8, and 9), oleanane (10 and 13–17) and lupane (18 and 19). Their structures were elucidated via a comprehensive analysis of the HRESIMS, NMR, and ECD data, as well as quantum chemical calculations of NMR parameters. Notably, compounds 1–5, 10–15, and 19 possessed an unusual 3,19 (or 25)-hemiketal structure bridging over ring A, while the remaining compounds were classified as 3-oxotriterpenoids. The skeletal diversity observed in these compounds was further elaborated from a biosynthetic perspective. Subsequently, the protective effects of fourteen compounds (1, 3, 4, 6–9, 11–14, and 16–18) against HF were evaluated using zebrafish models of isoproterenol-induced HF at a concentration of 1 μg/mL. Remarkably, all fourteen compounds significantly ameliorated pericardial edema, with five compounds (3, 6, 11, 14, and 16) also attenuating impaired cardiac output (CO), and eight compounds (1, 3, 4, 7–9, 14, and 16) inhibiting cardiomyocyte apoptosis. Notably, certain compounds even restored the impaired pericardium and CO to near-normal levels. These findings highlight the therapeutic potential of triterpenoids derived from R. chinensis as promising agents for the treatment of HF.