Enterolactone inhibits the growth of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas in the rat.

The inverse association between a high enterolactone (ENL) concentration in both urine and serum, and the risk of breast cancer found in epidemiological studies suggests a chemopreventive action for ENL. However, no causal relationship has been established in clinical studies or in experimental models for breast cancer. In the present study, the potential chemopreventive action of p.o. administered ENL (1 or 10 mg/kg of body weight) was tested in 7,12-dimethylbenz(a)anthracene-induced mammary cancers of the rat. Rats were maintained on a standard open-formula chow diet. Daily p.o. administration of ENL at a dose of 10 mg/kg of body weight for 7 weeks significantly inhibited tumor growth. The growth-inhibitory effect of ENL was more pronounced on the new tumors, which developed during the treatment period, but ENL also inhibited the growth of those tumors established before the start of the lignan administration. The rat serum concentration of ENL, which illustrated a permanent positive effect on breast cancer growth, was 0.4 microM, which is >10-fold as compared with the serum concentrations found in the general human population. The effect of ENL was not restricted to any specific histological tumor type. ENL was demonstrated to act as a weak aromatase inhibitor in vitro and to reduce the relative uterine weight of the 7,12-dimethylbenz(a)anthracene-treated nonovariectomized rats. However, in a short-term assay ENL had no effect on the uterine growth of the intact or androstenedione-treated immature rats. Thus, the mechanism of the ENL action and its minimum or optimal daily dose remains to be clarified.

Synthesis of (-)-matairesinol, (-)-enterolactone, and (-)-enterodiol from the natural lignan hydroxymatairesinol.

[reaction: see text] We describe here a four-step semisynthetic method for the preparation of enantiomerically pure (-)-enterolactone starting from the readily available lignan hydroxymatairesinol from Norway spruce (Picea abies). Hydroxymatairesinol was first hydrogenated to matairesinol. Matairesinol was esterified to afford the matairesinyl 4,4'-bistriflate, which was deoxygenated by palladium-catalyzed reduction to 3,3'-dimethylenterolactone. Demethylation of 3,3'-dimethylenterolactone and reduction with LiAlH(4) yielded (-)-enterolactone and (-)-enterodiol, respectively.

Conformation of the galactose ring adopted in solution and in crystalline form as determined by experimental and DFT 1H NMR and single-crystal X-ray analysis.

The solution-state conformations of various galactose derivatives were determined by comparison of the experimental (1)H-(1)H vicinal coupling constants to those calculated using density functional theory (DFT) at the B3LYP/cc-pVTZ//B3LYP/6-31G(d,p) level of theory. The agreement between the experimental and calculated vicinal coupling constants for 1,2:3,4-di-O-isopropylidene-alpha-d-galactopyranose was good, thereby confirming an (O)S(2) skew conformation for it and its derivatives on the basis of their similar observed couplings. Single-crystal X-ray analysis of 1,2:3,4-di-O-isopropylidene-6-O-(3,4,6-tri-O-acetyl-2-deoxy-2-N-phthalimido-beta-d-glucopyranosyl)-alpha-d-galactopyranose and 1,2,3,4,6-penta-O-acetyl-alpha-d-galactopyranose provided (O)S(2) and (4)C(1) conformations, respectively, for the galactose ring in the solid state. The solid-state structures proved to be suitable starting structures for further DFT structure refinement or for immediate calculation of the coupling constants.