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

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.