An X-ray crystallographic study of the nonsteroidal contraceptive agent centchroman.
We have determined an X-ray crystal structure for the N-methyl iodide derivative of the nonsteroidal contraceptive centchroman. The pendant aromatic substituents on C-3 and C-4 of the chroman system are nearly perpendicular to the plane of the chroman system, an orientation expected in such a chroman, but perturbed to some degree by the gem dimethyl substituents at C-2. Structural superposition with other nonsteroidal antiestrogens, tamoxifen and nafoxidine, shows a similar disposition of the tertiary amine side chains responsible for antagonist activity. The aryl rings also show good superposition, but in contrast to tamoxifen and nafoxidine, which have the potential for ring double bond conjugation, the centchroman aryl rings show a larger dihedral twist. While different superpositions between the enantiomers of centchroman and the bioactive enantiomer of estradiol (d-estradiol, 8 beta,9 alpha,13 beta,14 alpha,17 beta) are possible, when the chroman ring system is positioned over the AB rings of estradiol, then (3R,4R)-centchroman makes the best fit. The aryl substituents in both enantiomers make comparable overlays with the steroidal skeleton, but the axial methyl group at C-2 in (3R,4R)-centchroman is directed downward along the C-7 alpha axis of estradiol, a site where many substituents are known to be well tolerated by the estrogen receptor, while in the 3S,4S-enantiomer, this methyl group is projected upward. Thus, we suggest that the bioactive l-enantiomer of centchroman will have the 3R,4R absolute configuration.
Ray
S
S
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow, India.
Tandon
A
A
Dwivedy
I
I
Wilson
S R
SR
O'Neil
J P
JP
Katzenellenbogen
J A
JA
D002486:Centchroman / Q000737:chemistry* / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D004958:Estradiol / Q000378:metabolism; D007454:Iodides / Q000737:chemistry; D008745:Methylation; D008968:Molecular Conformation; D015394:Molecular Structure; D009256:Nafoxidine / Q000737:chemistry; D011960:Receptors, Estrogen / Q000378:metabolism; D013237:Stereoisomerism; D013629:Tamoxifen / Q000737:chemistry
D007454:Iodides; D011960:Receptors, Estrogen; D013629:Tamoxifen; D002486:Centchroman; D009256:Nafoxidine; D004958:Estradiol