title: New structure-activity relationships of A- and D-ring modified steroidal aromatase inhibitors: design, synthesis, and biochemical evaluation.
abstract: A- and D-ring androstenedione derivatives were synthesized and tested for their abilities to inhibit aromatase. In one series, C-3 hydroxyl derivatives were studied leading to a very active compound, when the C-3 hydroxyl group assumes 3β stereochemistry (1, IC(50) = 0.18 μM). In a second series, the influence of double bonds or epoxide functions in different positions along the A-ring was studied. Among epoxides, the 3,4-epoxide 15 showed the best activity (IC(50) = 0.145 μM) revealing the possibility of the 3,4-oxiran oxygen resembling the C-3 carbonyl group of androstenedione. Among olefins, the 4,5-olefin 12 (IC(50) = 0.135 μM) revealed the best activity, pointing out the importance of planarity in the A,B-ring junction near C-5. C-4 acetoxy and acetylsalicyloxy derivatives were also studied showing that bulky substituents in C-4 diminish the activity. In addition, IFD simulations helped to explain the recognition of the C-3 hydroxyl derivatives (1 and 2) as well as 15 within the enzyme.
authors.affiliation: CEF, Center for Pharmaceutical Studies, Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Varela
authors.forename: Elisiário J
authors.initials: EJ
authors.lastname: Tavares da Silva
authors.forename: Cristina
authors.initials: C
authors.lastname: Amaral
authors.forename: Georgina
authors.initials: G
authors.lastname: Correia da Silva
authors.forename: Teresa
authors.initials: T
authors.lastname: Baptista
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Giosuè
authors.initials: G
authors.lastname: Costa
authors.forename: Rui A
authors.initials: RA
authors.lastname: Carvalho
authors.forename: Natércia A A
authors.initials: NA
authors.lastname: Teixeira
authors.forename: Fernanda M F
authors.initials: FM
authors.lastname: Roleira
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D004852:Epoxy Compounds; D000735:Androstenedione; D001141:Aromatase