Structure-activity relationship of antiestrogens. Effect of the side chain and its position on activity of 2,3-diaryl-2H-1-benzopyrans

Abstract

A series of 2,3-diaryl-2H-1-benzopyrans carrying a tertiary aminoethoxy chain at the ortho, meta, or para position of 2-phenyl or an alkyl at position 4 of the pyran ring were synthesized and evaluated for their affinity for estrogen receptor (ER) and for microsomal antiestrogen specific binding site and for their uterotrophic-antiuterotrophic activities in rodents. The analogues bearing the side chain at the para position of 2-phenyl were found to be active while those substituted at the meta and ortho positions were inactive as ER ligands as well as estrogen agonists-antagonists. Among para-substituted ethers, the 2-piperidinoethoxy analogue 5 was found to be a more effective antiestrogen than the corresponding pyrrolidino, dimethylamino, and related analogues. Incorporation of a methyl or an ethyl at C4 in the pyran nucleus was found to increase receptor affinity of the prototypes. The ethyl was also found to potentiate agonist activity of the prototype while abolishing its antagonist activity. The piperidino analogue 5 was found to be a better antiestrogen than tamoxifen as well as LY-117018 in rats as well as mice. The prototypes were also found to have high affinity for the microsomal antiestrogen specific binding sites. The benzopyrans have thus emerged as a new group of potent antiestrogens.

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

“…The benzopyran-core docks in the ligand binding domain of both ER-α and ER-ß, but in opposite orientations, with several-fold ER-ß selectivity [21]. Since ER-ß has been assigned an important regulatory role in prostatic hyperplasia [30], we selected two molecules from the Institute's library of benzopyran-SERMs [22][23][24] that apparently emerged promising subsequent to the characterization of estrogen signaling in male and the discovery of ER-ß in prostate [31]. We selected DL-2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-2 H-1-benzopyran (BP/CDRI-85/287) from the Institute's SERM library of substituted benzopyrans on the basis of its low ER-α binding affinity (0.3% of estradiol; 23, 32) yet potent anti-implantation activity (which depends on ER-α antagonism).…”

“…Nevertheless, the activity of phyto-SERMs can by potentiated quite appreciably by structural modifications of its ER-ß selective benzopyran moiety [20,21]. Designed synthesis of a series of potent benzopyran-SERMs was carried out at the Central Drug Research Institute [22][23][24], before the discovery of ER-ß, essentially for female contraception. We selected two differently substituted benzopyran structures from the Institute's SERM-library: DL-2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-2 H-1-benzopyran (CDRI 85/287) and ormeloxifene ( Fig.…”

“…We selected two differently substituted benzopyran structures from the Institute's SERM-library: DL-2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-2 H-1-benzopyran (CDRI 85/287) and ormeloxifene ( Fig. 1) through judicious evaluation of their structure-activity-relationships [23,25], and thereby predicting their possible action against prostatic cells in light of recently published research on benzopyran-SERMs [21]. The effect of both of these molecules on human BPHderived stromal cells in vitro, BPH tissue explants cultures ex vivo and prostate of adult mature rats in vivo was studied in comparison with tamoxifen.…”

The regulation of Hh/Gli1 signaling cascade involves Gsk3β- mediated mechanism in estrogen-derived endometrial hyperplasia

“…Anti-estrogenic agent K1 (2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo (b) pyran) was synthesized by Medicinal Chemists of the CSIR-CDRI, Lucknow 50, 51 .…”

Synthesis and biological evaluation of 2,3,4-triarylbenzopyran derivatives as SERM and therapeutic agent for breast cancer

“…Dihydrobenzopyran-4-one 2 was prepared by base catalyzed condensation of 4-hydroxybenzaldehyde with 2 0 -hydroxy-2-phenylacetophenone 1 by a known method. 16 Chalcone 3 as side product was also formed along with compound 2 and could be easily separated by column chromatography.…”