Bistaxascendins A–G, Abietane Diterpenoid Dimers from Taxodium ascendens , Inducing Mitophagy in Colorectal Cancer Cells

Seven novel abietane-type diterpenoid dimers (ADDs), bistaxascendins A-G (1-7), and two known analogues (8 and 9) were isolated from the cones of Taxodium ascendens. Their structures were assigned through analysis of detailed spectroscopic data, X-ray crystallography, and quantum chemical calculations. Particularly, compound 1 is an unprecedented 6-O-8' and 7-O-7' angularly fused dioxygen-bridged ADD, while compound 6 represents the first example of an ADD connected by a 7-O-6' ether bond. The isolated compounds were systematically evaluated for cytotoxicity against human colorectal cancer cell lines via the MTT assay. Compounds 4 and 8 demonstrated dose-dependent antiproliferative efficacy against HCT116, SW480, and RKO cells, with IC₅₀ of 4.6-17.3 μM. Compound 8 displayed the most potent antiproliferative activity, with IC₅₀ values of 4.6 ± 0.2 μM, 5.1 ± 0.2 μM, and 5.6 ± 0.2 μM. Mechanistic studies revealed that compound 8 activated PINK1/Parkin-mediated mitophagy, as evidenced by upregulated autophagosomal markers and enhanced autophagic and mitophagic flux, indicating compound 8 as a promising lead compound for mitophagy-targeted colorectal cancer therapy.