Cyclomyrsinane and premyrsinane diterpenes from Euphorbia falcata modulate resistance of cancer cells to doxorubicin

Two new and one known cyclomyrsinane-type diterpenes (1–3) were isolated from the methanol extract of the whole, undried plant of Euphorbia falcata, native to Hungary. The structures and relative configuration of the compounds were established on the basis of extensive spectroscopic analysis, including HRESIMS and one- and two-dimensional NMR techniques. These compounds are hexa- and heptaesters of diterpene polyols, esterified with acetic, propanoic, isobutanoic, 2-methylbutanoic, and benzoic acids. This type of diterpenes was previously detected only in three Euphorbia species (Euphorbia teheranica, Euphorbia seguieriana, and Euphorbia prolifera). The compounds, together with premyrsinanes isolated previously from this plant were evaluated for their antiproliferative activity against HeLa, Ishikawa, and MCF7 mouse lymphoma cells, and for their capacity to modulate resistance to doxorubicin in L5178 mouse lymphoma cells that over-express the MDR1 efflux pump. Compounds did not show substantial antiproliferative activity against any of the tested cell lines. However all compounds act in a mild to a very strong synergism with doxorubicin against the MDR mouse lymphoma cell line.