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

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Carla Varela (Author) Other; Elisiario J T Tavares da Silva (Author) Other; Cristina Amaral (Author) Other; Georgina Correia da Silva (Author) FFUP; Teresa Baptista (Author) Other; Stefano Alcaro (Author) Other; Giosue Costa (Author) Other; Rui A Carvalho (Author) Other; Natercia A A Teixeira (Author) FFUP; Fernanda M F Roleira (Author) Other

Journal

Title: Journal of Medicinal Chemistry

Vol. 55

Pages: 3992-4002

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 52 Citations

Scopus - 51 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-002-AZE

DOI: 10.1021/jm300262w

Abstract (EN): 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 3 beta stereochemistry (1, IC50 = 0.18 mu M). 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 mu M) 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 mu M) 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11