New Structure–Activity Relationships of A- and D-Ring Modified Steroidal Aromatase Inhibitors: Design, Synthesis, and Biochemical Evaluation

• Published in: Journal of medicinal chemistry Vol. 55; no. 8; pp. 3992 - 4002
• Main Authors: Varela, Carla, Tavares da Silva, Elisiário J, Amaral, Cristina, Correia da Silva, Georgina, Baptista, Teresa, Alcaro, Stefano, Costa, Giosuè, Carvalho, Rui A, Teixeira, Natércia A. A, Roleira, Fernanda M. F
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.04.2012; Amer Chemical Soc
• Subjects: Androstenedione - analogs & derivatives; Androstenedione - chemical synthesis; Androstenedione - pharmacology; Aromatase - metabolism; Aromatase Inhibitors - chemical synthesis; Aromatase Inhibitors - chemistry; Aromatase Inhibitors - pharmacology; Binding Sites; Chemistry, Medicinal; Epoxy Compounds - chemical synthesis; Epoxy Compounds - pharmacology; Female; Humans; Inhibitory Concentration 50; Kinetics; Life Sciences & Biomedicine; Microsomes - enzymology; Models, Molecular; Pharmacology & Pharmacy; Placenta - enzymology; Pregnancy; Science & Technology; Structure-Activity Relationship; BREAST-CANCER; RECEPTOR; ANALOGS; BIOLOGICAL-ACTIVITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300262w

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, IC50 = 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 (IC50 = 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 (IC50 = 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.