Triketone-acylphloroglucinol-monoterpenoid hybrids from Callistemon viminalis, a new structural template of anti-cardiac hypertrophy

Abstract

Seven new β-triketone-acylphloroglucinol-monoterpenoid hybrids, namely callistevimones A-G (1–7), were isolated from Callistemon viminalis fruits. Their structures and absolute stereochemistry were accomplished through a comprehensive analytical method involving mass spectrometry, NMR, ECD calculation, QM-NMR calculation, and single-crystal X-ray crystallography. Compounds 1 and 2 are first examples of β-triketone-acylphloroglucinol-phellandrene with an enlarged-ring. Subsequently, the effects of these compounds on cardiac hypertrophy and heart failure were investigated in vitro for the first time. The results showed that compounds 2, and 5–7 significantly reversed isoinduced hypertrophic phenotype and the reduction of mitochondrial membrane potential in AC16 cells. Furthermore, these compounds significantly increased the mRNA expression and protein expression of MPC1 (mitochondrial pyruvate carrier 1), an emerging mediator of heart failure. Concurrently, these compounds increased glucose consumption, glycolysis, and the transportation of pyruvate into mitochondria in AC16 cells using ¹³C₆-labeled glucose and ¹³C₃-labeled pyruvate tracing. In conclusion, compounds 2 and 5–7 are potential for reversing isoinduced cardiac hypertrophy and energy metabolism disorders by increasing MPC1 activity, thus having potential therapeutic implications for the treatment of cardiac hypertrophy and heart failure.