Tagalide A and tagalol A, naturally occurring 5/6/6/6- and 5/6/6-fused cyclic dolabrane-type diterpenes: a new insight into the anti-breast cancer activity of the dolabrane scaffold

Abstract

Tagalide A (1) and tagalol A (2), representing dolabrane-type diterpenes with unprecedented ring-A/B/C/D- and ring-A/B/C-fused cores (vii–viii), respectively, were isolated from the Chinese mangrove, Ceriops tagal. The relative and absolute configurations of these dolabranes were unambiguously established by HRESIMS, extensive NMR investigations, and quantum-chemical ¹³C NMR and ECD calculations. Most notably, 1 exhibited cytotoxicities against triple-negative breast cancer (TNBC) cell lines, MD-MBA-453 (IC₅₀ = 1.73 μM) and MD-MBA-231 (IC₅₀ = 8.12 μM). Investigation of the mechanisms on MD-MBA-453 cells revealed that 1 induces ROS-mediated apoptosis and cell-cycle arrest in the G2/M phase. It suppresses the phosphorylation of JAK2 and STAT3, but enhances that of AKT and ERK. The 5,6-dihydrobenzofuran-2(4H)-one-7-carbaldehyde moiety of 1 is hitherto the most potent anticancer pharmacophore for the ring-A-centred western part of the dolabrane scaffold against the above-mentioned TNBC cells.