Chemical and pharmacological investigation of macrocyclic diterpenoids isolated from Euphorbia species.

Abstract

Eight macrocyclic diterpenoids were isolated from whole plants of E. esula, E. salicifolia and E. serrulata. The chemical structures of the compounds were elucidated by mass spectrometry, high-field nuclear magnetic resonance techniques. Spectral analyses revealed that the compounds are new members of the group of jatrophane diterpenes except compound 5, which is based on a modified 5-13 fused jatrophane skeleton. All compounds are highly functionalized with acetyl, benzoyl, isobutanoyl and nicotinoyl groups. The crude dichloromethane extracts and the pure compounds were subjected to pro-inflammatory assay. The extracts exhibited mouse irritant activity, with ID₅₀^4h values of 56-325 µg per ear. Compounds 1-4 were inactive up to a dose of 200 µg per ear, indicating that the jatrophane-type compounds do not play a significant role in the skin irritant activity of Euphorbia species. The antiproliferative and multidrug-resistance-reversing (mdr) activities of compounds 1-8 were evaluated on mouse lymphoma cells. The compounds inhibited cell growth. The growth inhibitory activity of compounds 2, 3, 4, 5, 7 and 8 was more potent against human mdr gene-transfected cells (IC₅₀ values of 1.4-3.3 µg/ml) than against parental cells (IC₅₀ values of 5.6-9.8 µg/ml). Only compound 1 displayed a marginal antiproliferative effect in both tests.