Highly Aromatic Norditerpenoid Heterodimers and Monomers from Trigonostemon fragilis

Abstract

Four new norditerpenoid heterodimers with different dimerization patterns—namely, trigofragiloids A–C (denoted as compounds 1–3) and (+)- and (−)-trigofragiloid D (compound 4)—and three new phenanthrenone norditerpenoids—namely, trigofragiloids E–G (compounds 5–7)—were isolated from Trigonostemon fragilis. Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid; they have been identified as class 2 atropisomers by means of quantum chemical calculations. Compound 3 is an unprecedented phenylpropanoid–norditerpenoid adduct with a new dimerization pattern. Compounds (+)- and (−)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers. Inspired by the structure elucidation of compound 4, two co-occurring analogues, actephilol A and epiactephilol A, were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers, (+)- and (−)-8 and (+)- and (−)-9, respectively. Their structures were characterized using a combined method. Notably, compound 7 exhibits remarkable adenosine triphosphate-citrate lyase (ACLY) inhibition with a half-maximal inhibition concentration (IC₅₀) value of (0.46 ± 0.11) μmol∙L⁻¹, as active as the positive control BMS-303141, and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.