Lignans Interfering with 5α-Dihydrotestosterone Binding to Human Sex Hormone-Binding Globulin

Abstract
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 5α-dihydrotestosterone (DHT) to human sex hormone-binding globulin (SHBG). (−)-3,4-Divanillyltetrahydrofuran (1) has the highest binding affinity (Ka = 3.2 ± 1.7 × 106 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.

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