Cis isomer of centchroman — A selective ligand for the microsomal antiestrogen binding site

Saeed, Ashraf; Durani, Neelam; Durani, S.; Ray, Suprabhat; Kapil, R. S.

doi:10.1016/s0006-291x(84)80374-5

Cited by 7 publications

(4 citation statements)

References 12 publications

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“…The presence of a second methyl group at this position is detrimental, as 3,4-cis-chroman (RBA: 0.0008; 6), stereoisomer of centchroman, is inactive at 50 mg/kg dose, 22,130 although its RBA for microsomal antiestrogen binding sites (46 AE 17) is at least 46,000-fold greater than that for ERs, in comparison to only about four-fold greater af®nity in case of 3,4-trans-centchroman (RBA-AEBS: 19 AE 5; RBA-ER: 5.42 AE 1.45). 133 NMR studies also reveal markedly different solution conformation of this molecule, due probably to the in¯uence of a second methyl group, than monomethyl analog, as here pyran ring appears to have a distorted conformation with C-3 and C-4 almost eclipsed. Its lack of receptor af®nity is due to mutual mismatch of these residues with corresponding binding regions of the receptor.…”

Section: S T R U C T U R E -A C T I V I T Y R E L a T I O N S H I Pmentioning

confidence: 82%

Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone‐related clinical disorders

Singh

2001

Medicinal Research Reviews

134

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DL-Centchroman (67/20; INN: Ormeloxifene) synthesized at the Central Drug Research Institute, Lucknow, is a nonsteroidal once-a-week oral contraceptive. It was introduced in Delhi in July, 1991, marketed in India in 1992 as Saheli and Choice-7 (Hindustan Latex Ltd., Thiruvananthapuram) and Centron (Torrent Pharmaceuticals India Ltd., Ahmedabad), and included in the National Family Welfare Programme in 1995.5 According to post-marketing surveillance, approximately 100,000 women were using this pill and approximately 1100,000 menstrual cycles were covered until 1996. It is a unique need-oriented contraceptive being effective when taken immediately after coitus or routinely as a weekly pill and has the advantage of less frequent administration. Its contraceptive action is quickly reversible. It has long terminal serum halflife of 168 hr in women and exhibits duration of anti-implantation/estrogen antagonistic action of 120 hr, despite a short (24.1 hr) serum halflife, in the rat. In lactating women, it is excreted in milk in quantities considered unlikely to cause any deleterious effect on suckling babies. In phase II and III multicentric trials as a contraceptive, children born of method-and-user failure pregnancies showed normal milestones, without any congenital anomaly. Reports of its promising action in the management of certain hormone-related clinical disorders are available. It has an excellent therapeutic index and is considered safe for chronic administration.

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Section: S T R U C T U R E -A C T I V I T Y R E L a T I O N S H I Pmentioning

confidence: 82%

Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone‐related clinical disorders

Singh

2001

Medicinal Research Reviews

134

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“…Ormeloxifene (International Nonproprietary Name for Centchroman) was synthesized [18] at this institute. Raloxifene was a generous gift from M/s.…”

Section: Chemicalsmentioning

confidence: 99%

Effect of ormeloxifene on ovariectomy-induced bone resorption, osteoclast differentiation and apoptosis and TGF beta-3 expression

Murthy

Sengupta

Sharma

et al. 2006

The Journal of Steroid Biochemistry and Molecular Biology

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“…Palladium was filtered off through Celite and the solvent was evaporated off to give a colorless mixture of three products which was separated by flash chromatography on silica (eluent, chloroform/hexane = 1:1). The desired product was recrystallized from methanol yielding white crystals of 7a (1.5 g, 75%): mp 72-73 °C; NMR (ppm) 2.83-3.43 (2q, 2 H, CH2 at C-2), 3.85 (s, 3 H, OCH3), 4.75 (dd, 1 , H-2), 6.47-7.56 (m, 7 H, ArH); MS m/z 290, 288 (M+, 16,48), 254 (15), 177 (35), 125 A similar procedure to that described for 7a was used for the preparation of 7b-d and the yields and physical constants are given in Table II.…”

Section: Table VIII Effect Ofmentioning

confidence: 99%

Synthesis of 2-(p-chlorobenzyl)-3-aryl-6-methoxybenzofurans as selective ligands for antiestrogen-binding sites. Effects on cell proliferation and cholesterol synthesis

Teo

Kon²,

Sim³

et al. 1992

J. Med. Chem.

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A series of nonsteroidal compounds, 2-(p-chlorobenzyl)-3-aryl-6- methoxybenzofurans derived from the 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones has been synthesized. The key steps in the synthesis were reactions of 2-(p-chlorobenzyl)-6-methoxy-3(2H)-benzofuranones with the arylorganometallic reagents followed by dehydration of the resulting carbinols. The benzofurans are ligands for antiestrogen-binding sites (AEBS) and display no significant interaction with the estrogen receptor (ER). All bind to AEBS with equivalent or greater affinity than tamoxifen. These compounds decrease [3H]thymidine incorporation in AEBS-containing EL4 lymphoid cells and MCF7 breast cancer cells in a concentration-dependent manner between 10(-8) and 10(-6) M and are generally more inhibitory than tamoxifen. In contrast, they have no effect on [3H]thymidine incorporation by an AEBS-deficient variant of the MCF7 cell line, RTx6. The present findings of (1) selective and high affinity binding of the benzofurans to AEBS, (2) their concentration-dependent inhibition of [3H]thymidine incorporation in AEBS-containing cells, and (3) their lack of antiproliferative effect in an AEBS-deficient cell line suggest a functional role for AEBS in mediating the antigrowth effect of these compounds. Two of the more active benzofuran compounds also significantly inhibited de novo cholesterol biosynthesis in EL4 cells which lack ER. This effect could be obtained after 5 h of treatment and preceded significant loss of cell viability. This is the first demonstration that selective ligands of AEBS (other than the known nonsteroidal antiestrogens) interfere with cholesterol biosynthesis-an action that may contribute to their antigrowth effect.

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Cis isomer of centchroman — A selective ligand for the microsomal antiestrogen binding site

Cited by 7 publications

References 12 publications

Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone‐related clinical disorders

Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone‐related clinical disorders

Effect of ormeloxifene on ovariectomy-induced bone resorption, osteoclast differentiation and apoptosis and TGF beta-3 expression

Synthesis of 2-(p-chlorobenzyl)-3-aryl-6-methoxybenzofurans as selective ligands for antiestrogen-binding sites. Effects on cell proliferation and cholesterol synthesis

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