An X-ray Crystallographic Study of the Nonsteroidal Contraceptive Agent Centchroman

Abstract

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.

TM‐25659 enhances osteogenic differentiation and suppresses adipogenic differentiation by modulating the transcriptional co‐activator TAZ

“…Many reports have found that the ligand binding to nuclear hormone receptors such as PPARα, PPARβ, PPARγ, retinoid acid receptor (RAR) and oestrogen receptor (ER) increased DNA‐binding, dimerization and transcriptional activities (Jans, 1994; MacLean et al ., 1997; Clevenger, 2003; Claessens and Gewirth, 2004; Smith and O'Malley, 2004). For example, binding of a selective oestrogen modulator, tamoxifen, to ERs induced conformational alterations, thus affecting the ability of ERs to interact with other proteins, such as co‐activators and co‐repressors and to modulate target gene transcription (Kuroda et al ., 1985; Ray et al ., 1994; Brzozowski et al ., 1997; Shiau et al ., 1998). Likewise, TM‐25659 may directly bind to TAZ and promote conformational changes and subsequent interaction with various transcription factors such as RUNX2 and PPARγ.…”

In vitro anti-resorptive activity and prevention of ovariectomy-induced osteoporosis in female Sprague–Dawley rats by ormeloxifene, a selective estrogen receptor modulator

“…Possibly, administration of 1.25 mg/kg per day dose of ormeloxifene over a longer period as would be required in clinical condition or titration of its dose/schedule might provide the regimen for optimal protection against post-menopausal bone loss, without significantly stimulating endometrial/breast tissue. Levormeloxifene, the l-analog of this molecule, which is a more potent receptor binder with relative binding affinity (RBA: 15.7 ± 3.1% of estradiol-17␤) to rat uterine cytosol estrogen receptors (ER) [25], has recently been reported to inhibit bone loss in estrogen-deficient animal models [26]. In a double blind clinical trial, decrease in serum total alkaline phosphatase and urine excretion of C-terminal extension peptides has also been observed in post-menopausal women treated for 35 (20,80 or 160 mg) or 56 (40 or 80 mg) days, indicating its estrogen-like bone preserving effect, but caused endometrial thickening due to fluid retention, without evidence of proliferation or hyperplasia [24].…”

Reactivity and Antiproliferative Activity of Ferrocenyl–Tamoxifen Adducts with Cyclodextrins against Hormone‐Independent Breast‐Cancer Cell Lines

“…As a consequence, the search for related but different agents has intensified considerably over the last few years. [4][5][6][7][8] Recently, it was discovered that grafting a ferrocenyl unit onto the tamoxifen skeleton allowed the preparation of a new and promising class of ferrocifen-type breast-cancer drug candidates. [9][10][11][12] These new molecules, called "hydroxyferrocifens" by analogy to tamoxifen, present the advantage of exhibiting dual functionality.…”

“…However, tamoxifen is active only against tumors that are estrogen‐receptor positive (ER+), and frequently gives rise to resistance after prolonged use. As a consequence, the search for related but different agents has intensified considerably over the last few years 4–8. Recently, it was discovered that grafting a ferrocenyl unit onto the tamoxifen skeleton allowed the preparation of a new and promising class of ferrocifen‐type breast‐cancer drug candidates 9–12.…”