Spiroamentotaxols A–D: unprecedented 6/6/6/5/6/6/6/6 spiro-octacyclic bis-diterpene heterodimers from the endangered conifer Amentotaxus yunnanensis and their bioactivities

Abstract

As a new chemical class of bis-diterpene heterodimers, spiroamentotaxols A–D (1–4) are characterized by a complex 6/6/6/5/6/6/6/6 spiro-octacyclic ring system, which is likely biogenetically derived from a Diels–Alder [4 + 2] cycloaddition between an ent-kaurene and a C₂₀-norabietane. The spiroamentotaxols possess a distinctive spiro[bicyclo[3.2.1]octane-7,2′-bicyclo[2.2.2]octene] motif. Through the application of molecular ion networking (MoIN), these intermolecular Diels–Alder isomers were isolated from the renewable twigs and needles of the endangered Chinese conifer Amentotaxus yunnanensis. Their chemical structures were elucidated using spectroscopic methods, electronic circular dichroism calculations, and X-ray diffraction analysis. From a structural diversity perspective, two semi-synthetic analogs, namely, 7′-deoxy-6′-en-spiroamentotaxol A (1a) and 7′-deoxy-spiroamentotaxol A (1b), were synthesized from the relatively major compound 1. These spiro-polycyclic compounds were evaluated for their in vitro anti-inflammatory and anticancer activities. In particular, compound 1 attenuated inflammation in both RAW 264.7 macrophage and BV2 microglial cells at a non-toxic concentration of 20 μM, with the lipopolysaccharide (LPS)-induced nitric oxide production inhibition rates of 46.66% and 32.37%, respectively. 1b exhibited efficacy against a panel of human cancer cell lines (A549, MCF7, HCT116, RKO, and HepG2), with IC₅₀ values ranging from 6.27 to 14.10 μM. In the case of HCT116 cells, 1b specifically influenced cell-cycle progression at the G2 phase and induced apoptosis. The findings highlight the importance of conserving plant species diversity as a means to sustain chemical diversity and serve as a potential source of new therapeutic agents for cancer treatment.