Lignans interfering with 5 alpha-dihydrotestosterone binding to human sex hormone-binding globulin.

The natural lignans (-)-3,4-divanillyltetrahydrofuran (1), (-)-matairesinol (2), (-)-secoisolariciresinol (3), (+/-)-enterolactone (4), (+/-)-enterodiol (5), and nordihydroguaiaretic acid (NDGA) (6) reduce the binding of 3H-labeled 5 alpha-dihydrotestosterone (DHT) to human sex hormone-binding globulin (SHBG). (-)-3,4-Divanillyltetrahydrofuran (1) has the highest binding affinity (Ka = 3.2 +/- 1.7 x 10(6)M-1) of all lignans investigated so far; the reversibility of its binding and a double reciprocal plot suggest a competitive inhibition of the SHBG-DHT interaction. Increasing hydrophobity in the aliphatic part of the lignans (butane-1,4-diol-butanolide-tetrahydrofuran structures) leads to higher binding affinity. In the aromatic part, a 3-methoxy-4-hydroxy substitution pattern is most effective for binding to SHBG.