Efficient NMR spectroscopy approach for the determination of the relative configuration of Δ5,6Δ11,12-jatrophane diterpenes and their chemotherapy sensitization activities

Abstract

Jatrophane diterpenes, a class of natural products exclusively found in the Euphorbiaceae family, are characterized by their distinctive trans-bicyclo[10.3.0]pentadecane scaffold. The relative configurations of jatrophane diterpenes are challenging to be determined solely based on the NOESY spectra due to the high flexibility and variable conformers of the 5/12-fused ring core. Phytochemical investigation of Euphorbia helioscopia L. led to the isolation of 36 macrocyclic diterpenes, including 34 jatrophane-type compounds (1–34). Notably, 1 was characterized as an undescribed compound and the NMR data of 2–9 were supplemented. In addition, the X-ray crystallographic structures of 2, 3 and 9 were successfully determined, providing unambiguously confirmation of their configuration. The present study categorized the isolated and literature-reported Δ^5,6Δ^11,12-jatrophane diterpenes into 10 structural types and summarized their NMR patterns. Based on this classification, an efficient NMR spectroscopic strategy for determining the relative configurations of Δ^5,6Δ^11,12-jatrophane diterpenes was developed. The inhibition of CHK1 phosphorylation enhances the sensitivity of tumor cells to chemotherapy drugs through blocking the cell cycle checkpoints. All the isolates were investigated for their inhibitory effects against camptothecin (CPT) -induced phosphorylation of CHK1 by the Western blotting assay. Moreover, a preliminary structure–activity relationship study of the isolates was conducted. Further mechanistic studies revealed that 23 enhanced the chemosensitivity of MCF-7 cells to CPT by inhibiting CHK1 and Wee1 phosphorylation and inducing PARP cleavage. The present study provided a new insight into jatrophane diterpenes as chemosensitizer agents.