Structure-activity relationships of new A,D-ring modified steroids as aromatase inhibitors: Design, synthesis, and biological activity evaluation

• Type: Article in International Scientific Journal
• Date: 2005

Authors

Cepa, MMDS (Author) Other; da Silva, EJT (Author) Other; Correia Da Silva, G (Author) FFUP; Roleira, FMF (Author) Other; Teixeira, NAA (Author) FFUP

Journal

Title: Journal of Medicinal Chemistry

Vol. 48

Pages: 6379-6385

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 53 Citations

Scopus - 71 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-000-0YM

DOI: 10.1021/jm050129p

Abstract (EN): Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New A,D-ring modified steroid analogues of formestane and testolactone were designed and synthesized and their biochemical activity was investigated in vitro in an attempt to find new aromatase inhibitors and to gain insight into their structure-activity relationships (SAR). All compounds tested were less active than formestane. However, the 3-deoxy steroidal olefin 3a and its epoxide derivative 4a proved to be strong competitive aromatase inhibitors (K-i = 50 and 38 nM and IC50 = 225 and 145 nM, respectively). According to our findings, the C-3 carbonyl group is not essential for anti-aromatase activity, but 5(x-stereochemistry and some planarity in the steroidal framework is required. Furthermore, modification of the steroidal cyclopentanone D-ring, by construction of a delta-lactone six-membered ring, decreases the inhibitory potency. From the results obtained, it may be concluded that the binding pocket of the active site of aromatase requires planarity in the region of the steroid A,B-rings and the D-ring structure is critical for the binding.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 7