Selective inhibition of aromatase by a dihydroisocoumarin from Xyris pterygoblephara

Abstract

Aromatase is a well-established target for the chemoprevention of breast cancer. The dihydroisocoumarin (3 R,4 R)-(-)-6-methoxy-1-oxo-3-pentyl-3,4-dihydro-1 H-isochromen-4-yl acetate (1) (IC 50 = 1.6 +/- 0.1 microM), isolated from aerial parts of Xyris pterygoblephara, showed aromatase inhibitory activity. The specificity of 1 was evaluated by inhibition assays with cytochrome P450 enzymes. CYP1A1 was inhibited modestly (IC 50 = 38.0 +/- 2.0 microM), while CYP2C8 and CYP3A4 enzymes were not affected. Dihydroisocoumarin 1 showed weak antiproliferative activity against MCF-7 (IC 50 = 66.9 +/- 2.3 microM) and LNCaP (IC 50 = 57.5 +/- 2.0 microM) cells and was inactive against LU-1 and HepG2 cells in culture. These results demonstrate the potential of dihydroisocoumarin 1 to serve as a selective aromatase inhibitor.

Figure 1

Dose-response studies of the inhibition of compound 1 on aromatase (CYP19) and CYP1A1. Results are the means of three assays, each one carried out in triplicate.

Chemical structure of dihydroisocoumarin (1) [(3R,4R)-(-)-6-methoxy-1-oxo-3-pentyl-3,4-dihydro-1H-isochromen-4-yl acetate]