Diterpene-phenylpropanoid hybrids and structurally diverse diterpenoid monomers from the endangered conifer Podocarpus annamiensis and their bioactivities.

In this phytochemical investigation, a total of 16 previously undescribed and 27 known diterpene-related compounds were isolated from the endangered Chinese endemic conifer Podocarpus annamiensis. Podoannamiacids A (1) and B (2) represent the first examples of a new chemical class of diterpene-phenylpropanoid hybrids characterized by a unique 7'-phenyl-7',8'-dihydrobenzofuran unit. This structure is hypothesized to be biogenetically derived through the formation of newly generated C-12-C-8' and C-13-O-C-7' bonds via a free radical coupling reaction between a totarane unit and a phenylpropanoid moiety. The remaining previously undescribed compounds are structurally diverse diterpenoid monomers, including totarane-type compounds 3-9. Notably, annamiacids C (3) and D (4) feature a rare dihydro-pyrane fragment, while annamiacids E (5) and F (6) contain a dihydro-furan and a β,γ-unsaturated-γ-lactone motif, respectively. Compounds 10-14 are classified as abietane-type diterpenes, whereas compounds 15 and 16 are categorized as sempervirane-type and podocarpane-type diterpenes, respectively. Their chemical structures were elucidated using spectroscopic data analysis, GIAO NMR calculations combined with DP4+ probability analyses, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Liquiditerpenoic acid A (30) exhibited inhibitory activity against ATP-citrate lyase (ACL) with an IC value of 5.0 μM. Similarly, 18-hydroxysempervirol (40) inhibited acetyl-CoA carboxylase 1 (ACC1) with an IC value of 14.41 μM. Additionally, rakanmakilactone I (43) demonstrated anti-neuroinflammatory effects in BV-2 cells, reducing NO release by 21.4 % at a concentration of 20 μM. The above findings, along with previously reported totarane-O-abietane (44) and abietane-O-abietane dissymmetric bis-diterpenes (45), further expand the understanding of the structural diversity and medicinal potential of this endangered conifer, offering a promising strategy for its sustainable utilization and conversation. This approach not only positions the species as a potential source for treating metabolic diseases but also encourages the further protection of these fragile plant resources.