NEW JATROPHANE DITERPENES FROM EUPHORBIA MONGOLICA WITH MULTIDRUG RESISTANCE MODULATING ACTIVITY

Diterpenes of the genus Euphorbia based on different skeletal types attracted interest because of their promising multidrug resistance reversing activity. Many compounds of the macrocyclic jatrophane-type significantly inhibit the overproduction of permeability glycoprotein (P-gp) in the plasma membrane of resistant tumour cells, reducing the intracellular accumulation of drugs. In our previous work we have reported the isolation of three jatrophane polyesters from Euphorbia mongolica Prokh. with anti-MDR activity. With the aim to find further efficient compounds, the minor diterpene constituents of E. mongolica were examined. From the dried, powdered plant material, originating from Govi Gurvan-Sajhan, Omnogovi (Mongolia), a lipophylic chloroform extract was prepared. Five compounds were isolated from this extract with a combination of multiple chromatographic methods (CC, VLC, CPC and HPLC). The structures were elucidated by HREIMS and NMR spectroscopy, including 1H NMR, JMOD, 1H-1H COSY, NOESY, HSQC and HMBC experiments. The isolated compounds, including four new natural products, are jatrophane-12-ene-9,14-diketo-polyesters esterified with acetic, propanoic, n-butyric, isobutyric and benzoic acids. The anti-MDR activities of the isolated compounds were assayed on human MDR gene transfected L5178 mouse lymphoma cells using the rhodamine exclusion test, and it was found that all compounds modulated the intracellular drug accumulation. Comparing the structures with the MDR modifying activity, expressed by fluorescence activity ratio, some structural requirements of the anti-MDR effect of the jatrophane polyesters were established. Acknowledgements: This work was supported by grant OTKA K72771