title: Aromatase inhibitors. Syntheses and structure-activity studies of novel pyridyl-substituted indanones, indans, and tetralins.
abstract: The (E)-2-(4-pyridylmethylene)-1-indanones(E)-1-(E)-5[(E)-1,H;(E)-2,4- OCH3; (E)-3,5-OCH3; (E)-4,4-OH;(E)-5,5-OH] were obtained by aldol condensation of the corresponding 1-indanones with 4-pyridinecarboxaldehyde, and in case of the OH compound (E)-4 subsequent ether cleavage of (E)-2. The synthesis of the (Z)-isomers (Z)-1-(Z)-3[(Z)-1,H;(Z)-2,4-OCH3; (Z)-3,5-OCH3] was accomplished by UV irradiation of the corresponding (E)-isomers. Catalytic hydrogenation of (E)-1-(E)-3 gave the 2-(4-pyridylmethyl)-1-indanones 6-8 (6, H; 7,4-OCH3; 8,5-OCH3). The 2-(4-pyridylmethyl)-substituted indans 11-13 (11,H; 12,4-OCH3; 13,5-OCH3) and the tetralins 16-19 (16,H;17,5-OCH3;18,6-OCH3;19,7-OCH3) were obtained by reduction of the corresponding ketones using N2H4/KOH. The 2-(4-pyridylmethyl)-substituted indanones 9 (4-OH) and 10 (5-OH), indans 14 (4-OH) and 15 (5-OH), and tetralins 20-22 (20,5-OH; 21,6-OH; 22,7-OH) were synthesized by ether cleavage of the corresponding OCH3 compounds. All compounds showed inhibition of human placental aromatase exhibiting relative potencies from 0.9 [(E)-4] to 163 [18; aminoglutethimide (AG) potency identical to 1]. Compounds 13 and 18 showed competitive type of inhibition and a type II difference spectrum, indicating the interaction of the pyridyl-N with the central Fe(III) ion of the cytochrome P450 heme component.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Fachrichtung 12.1 Pharmazeutische Chemie, Universität des Saarlandes, Saarbrücken, Germany.
authors.forename: R W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: H
authors.initials: H
authors.lastname: Bayer
authors.forename: G
authors.initials: G
authors.lastname: Grün
mesh_terms: D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D002417:Cattle; D005260:Female; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000201:enzymology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D014599:Uterus / Q000033:anatomy & histology
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D007189:Indans; D013764:Tetrahydronaphthalenes; D013739:Testosterone; D000735:Androstenedione; C013352:indacrinone; D001141:Aromatase