Design, synthesis, biological activity evaluation and structure-activity relationships of new steroidal aromatase inhibitors. The case of C-ring and 713 substituted steroids

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Roleira, FMF (Author) Other; Costa, SC (Author) Other; Gomes, AR (Author) Other; Varela, CL (Author) Other; Amaral, C (Author) Other; Augusto, TV (Author) Other; Georgina Correia da Silva (Author) FFUP; Romeo, I (Author) Other; Costa, G (Author) Other; Alcaro, S (Author) Other; Teixeira, N (Author) Other; Tavares-da-Silva, EJ (Author) Other

Journal

Title: Bioorganic Chemistry

Vol. 131

ISSN: 0045-2068

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 0 Citations

Scopus

Other information

Authenticus ID: P-00X-PNG

DOI: 10.1016/j.bioorg.2022.106286

Abstract (EN): In this work, new steroidal aromatase inhibitors (AIs) were designed, synthesized, and tested. In one approach, C -ring substituted steroids namely those functionalized at C-11 position with an alpha or 13 hydroxyl group or with a carbonyl group as well as C-9/C-11 steroidal olefins and epoxides were studied. It was found that the carbonyl group at C-11 is more beneficial for aromatase inhibition than the hydroxyl group, and that the C-ring epoxides were more potent than the C-ring olefins, leading to the discovery of a very strong AI, compound 7, with an IC50 of 0.011 mu M, better than Exemestane, the steroidal AI in clinical use, which presents an IC50 of 0.050 mu M. In another approach, we explored the biological activity of A-ring C-1/C-2 steroidal olefins and epoxides in relation to aromatase inhibition and compared it with the biological activity of C-ring C-9/C-11 steroidal olefins and epoxides. On the contrary to what was observed for the C-ring olefins and epoxides, the A-ring epoxides were less potent than A-ring olefins. Finally, the effect of 713 -methyl substitution on aromatase inhibition was compared with 7 alpha-methyl substitution, showing that 713 -methyl is better than 7 alpha-methyl substitution. Molecular modelling studies showed that the 713 -methyl on C-7 seems to protrude into the opening to the access channel of aromatase in comparison to the 7 alpha-methyl. This comparison led to find the best steroidal AI (12a) of this work with IC50 of 0.0058 mu M. Compound 12a showed higher aromatase inhibition capacity than two of the three AIs currently in clinical use.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11