Nonsteroidal estrogens: synthesis and estrogen receptor binding affinity of derivatives of (3R,4S)-3,4-bis(4-hydroxyphenyl)hexane (hexestrol) and (2R,3S)-2,3-bis(4-hydroxyphenyl)pentane (norhexestrol) functionalized on the side chain

• Published in: Journal of medicinal chemistry 1982-11, Vol.25 (11), p.1300-1307
• Main Authors: Landvatter, Scott W, Katzenellenbogen, J. A
• Format: Article
• Language: English
• Subjects: Animals; Estradiol Congeners - chemical synthesis; Estradiol Congeners - metabolism; Female; Hexestrol - analogs & derivatives; Hexestrol - chemical synthesis; Hexestrol - metabolism; In Vitro Techniques; Rats; Receptors, Estrogen - metabolism; Sheep; Uterine Contraction - drug effects; Uterus - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00353a006

A series of nonsteroidal, side-chain functionalized estrogens based on (3R*,4S*)-3,4-bis(4-hydroxyphenyl)hexane (hexestrol) and (2R*,3S*)-2,3-bis(4-hydroxyphenyl)pentane (norhexestrol) has been prepared; these include amide, diazo ketone, ester, alcohol, ketone, fluoro, bromo, iodo, and saturated hydrocarbon derivatives. Analysis of the binding affinity of these compounds to the uterine estrogen receptor, measured by competitive binding assay, reveals trends that can be related to the steric size, the hydrophobicity, and the hydrogen bond accepting character of the side-chain substituents. Comparison of binding affinities between norhexestrol and hexestrol derivatives indicates that, in general, the norhexestrols show significantly higher receptor binding affinities, making this series of compounds ideally suited as functional probes for the estrogen receptor.