Amide derivatives of 2,3-diarylacrylophenone as estrogen receptor binding ligands.

Substituted amidoalkyl derivatives of 2,3-diarylacrylophenones carrying the amide chain on the 3-aryl residue have been prepared by reacting corresponding phenolic 2,3-diarylacrylophenones with haloalkyl carboxylic acid esters, their hydrolysis and subsequent treatment with different alkyl amines. Compounds thus prepared were evaluated for their relative binding affinity (RBA) towards estrogen receptors (ER), estrogen agonistic and antagonistic activities. Out of eleven amide derivatives thus prepared, compounds 7, 13, 15-19, 23, 24 showed significant estrogen antagonistic activity. Interestingly the phenolic compound 7 and the acid ester 18 also exhibited estrogen inhibiting property. Majority of the dimethoxy derivatives (R = OCH(3)) showed significantly high estrogenic activity. In order to throw light on their SAR, In silico docking of the acrylophenone derivatives in the ligand binding site of the ERalpha and their comparison with pure steroidal estrogen antagonist ICI-164,384 and the non-steroidal antiestrogen raloxifene, was carried out. Crystal structure of compound 6 revealed relative trans-geometry of the 2(B) and 3(C) phenyl rings.

Rapid synthesis of 4-benzylidene and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans as potential selective estrogen receptor modulators (SERMs) using McMurry coupling reaction.

7-Methoxy-4-(4-methoxybenzylidene)-2-substituted phenyl-benzopyrans I and 4-[bis-(4-methoxyphenyl)-methylene-2-substituted phenyl-benzopyrans II carrying different alkylamino residues, designed as estrogen receptor (ER) binding ligands, were successfully synthesized through the McMurry coupling reaction of substituted benzaldehyde/substituted benzophenones and 2-hydroxyphenyl-7-methoxy-chroman-4-one in presence of lithium aluminum hydride and titanium (IV) chloride (LAH-TiCl(4)). Self-coupling of carbonyl reactants led to the formation of several side products. The prototypes were evaluated for their relative binding affinity (RBA), as well as their estrogenic and antiestrogenic activities. High order of estrogenic activity (>50% gain) observed with compounds 3, 7a, 7b, 7c, 8, and 10a and also their partial estrogen antagonistic activity (> or =15%) at the uterine level points toward successful designing of the compounds. Compounds 4, 7a, 7b, 7c, and 10a also possessed significant anticancer activity against human adenocarcinoma cell line (MCF-7 cell line) that may be related to their estrogen-dependent action.

Amide derivatives of 9,11-seco-estra-1,3,5(10)-trien-11-oic acid as modified orally active estrogen agonists with moderate antagonistic activity.

Synthesis of amide derivatives of 9,11-seco-estra-1,3,5(10)-trien-11-oic acid containing alkyl and aromatic amine residues has been carried out with an aim to prepare orally active estrogen antagonists. Modification of the estradiol molecule in the form of C-seco-amide derivatives has led to their high oral absorption. Compounds 7 an n-propyl amide, 8 an n-butyl amide, and 16 a p-anisidyl amide of C-seco-estrane showed significant estrogen antagonistic activity (>20%), while, the majority of compounds possessed high estrogen agonistic activity on oral administration at 10mg/kg dose in rats.