Structure-activity relationship of antiestrogens. A study using triarylbutenone, benzofuran, and triarylfuran analogs as models for triarylethylenes and triarylpropenones

Abstract

In a study of the structure-activity relationship (SAR) of antiestrogens use has been made of certain 1,2,3-triarylbutenones, of 2-arylbenzofurans carrying aryl or aroyl substituents at C3, and of 2,3,4-triarylfurans as conformationally constrained models for triarylethylene (TAE) and triarylpropenone (TAP) prototypes. The position-specific contributions of substituents to receptor affinity and to agonist-antagonist profiles were used as aids in characterizing the relative binding orientation of the prototypes. Although most compounds were found to be weak receptor ligands and poorly active in vivo, the following conclusions could be drawn about their SAR: (i) (Z)-TAPs and TAEs interact with the receptor in an analogous manner using the trans-stilbene core, with their agonist-antagonist profiles depending on the nature of other substructures. (ii) Incorporation into the benzofuran framework introduces a stereoelectronic constraint that compromises the normal binding interactions of TAE, as well as TAP, prototypes, resulting in their poor affinities and weak biological activities. (iii) (E)-TAPs can interact with the receptor through their S-cis conformation, but such a binding mode is unlikely to account for their behavior as antagonists.

Antiestrogens and Selective Estrogen Receptor Modulators as Multifunctional Medicines. 1. Receptor Interactions

“…The introduction of one ( 17 ) or two ( 18 ) strategically placed phenolic groups in the benzopyrans enhances ER binding, but the resulting compounds are completely devoid of estrogen agonist activity in the immature mouse uterine weight test while retaining antiestrogenic activity that is superior to LY117018 , ( 19 ), a raloxifene analogue. The structure−function relationships of a huge number of naphthalene, indene, benzofuran, and benzopyran ,, derivatives have been evaluated for both antiestrogenic and antifertility properties in rats and mice and form the foundation for medicinal chemistry in this area.

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Non-Steroidal Subtype Selective Estrogens

“…Furans have previously been described as potential antifertility agents, but no subtype selectivity was reported in these studies [64]. Furans having different substituents at the 3-position and a BSC attached to the 4-position were prepared.…”

Palladium-Catalyzed Tandem Annulation: A Strategy To Construct 2,3-Difunctionalized Benzofuran Derivatives in Ionic Liquids

“…4-((2-(4-Hexylphenyl)benzofuran-3-yl)methyl)oxetan-2-one (3ae): yield 85% (76.9 mg) as a yellow oil; R f 0.40 (petroleum ether/ EtOAc 5/1); 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (t, J = 7.2 Hz, 3H), 7.53 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 3H), 7.27 (d, J = 7.6 Hz, 1H), 5.91 (t, J = 8.0 Hz, 1H), 2.81 (dd, J = 16.8, 7.6 Hz, 2H), 2.74−2.60 (m, 4H), 1.69−1.62 (m, 2H), 1.40−1.30 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 176. 7, 154.4, 154.1, 144.8, 129.0, 128.0, 127.1, 126.8, 124.8, 123.1, 120.4, 112.9, 111.6, 76.0, 35.8, 31.7, 31.3, 29.6, 28.9, 28.6, 22.6, 14 7, 154.4, 154.0, 152.9, 127.9, 126.9, 126.8, 125.9, 124.8, 123.1, 120.5, 112.9, 111.6, 76.0, 34.9, 31.2, 29.6, 28.6 ppm; ν max (KBr)/cm −1 3057, 2959, 1778, 1619, 1509, 1455, 1400, 1135MS (EI) m/z 105, 119, 133, 154, 193, 207, 249, 281, 334 7, 160.0, 154.3, 154.1, 129.6, 126.9, 124.6, 123.1, 122.0, 120.3, 114.9, 112.1, 111.5, 76.1, 63.7, 29.6, 28.5, 14.8 ppm; ν max (KBr)/cm −1 3060, 2923, 1775, 1645, 5,163.4 (J = 249.2 Hz),154.4,152.9,130.1 (J = 8.4 Hz),126.6,125.9 (J = 3.2 Hz),125.1,123.3,120.5,116.2 (J = 21.7 Hz),113.3,111.7,75.7,29.5,28.5 ppm; ν max (KBr)/cm −1 3063, 2922,1775,1644,1508,1453,1416,1182,749 5, 154.5, 152.5, 135.7, 130.9, 129.3, 129.2, 128.6, 125.3, 123.4, 120.6, 113.9, 111.7, 75.6, 29.4, 28.6 ppm; ν max (KBr)/cm −1 3064, 2923, 1777, 1648…”

“…Consequently, palladiumcatalyzed tandem processes constitute an efficient strategy to synthesize an increasingly wide range of polyfunctionalized compounds. 4 In addition, 2,3-difunctionalized benzofurans are attractive synthetic targets because of their remarkable biological activities and potentiality of being pharmaceutical, 5 prompting development of many efficient synthetic methodologies for constructing this scaffold. Undoubtedly, 2-alkynylphenols are the most commonly used precursors to prepare this functionalized core backbone, for instance, cyclization of 2-alkynylphenol to the 3-metallobenzofuran intermediate that reacts further with an electrophile to produce the corresponding 2,3-difunctionalized benzofuran derivatives (Scheme 1, route a).…”