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C-6α- vs C-7α-Substituted Steroidal Aromatase Inhibitors: Which Is Better? Synthesis, Biochemical Evaluation, Docking Studies, and Structure-Activity Relationships.

Authors :
Roleira FMF
Varela C
Amaral C
Costa SC
Correia-da-Silva G
Moraca F
Costa G
Alcaro S
Teixeira NAA
Tavares da Silva EJ
Source :
Journal of medicinal chemistry [J Med Chem] 2019 Apr 11; Vol. 62 (7), pp. 3636-3657. Date of Electronic Publication: 2019 Mar 26.
Publication Year :
2019

Abstract

C-6α and C-7α androstanes were studied to disclose which position among them is more convenient to functionalize to reach superior aromatase inhibition. In the first series, the study of C-6 versus C-7 methyl derivatives led to the very active compound 9 with IC <subscript>50</subscript> of 0.06 μM and K <subscript>i</subscript> = 0.025 μM (competitive inhibition). In the second series, the study of C-6 versus C-7 allyl derivatives led to the best aromatase inhibitor 13 of this work with IC <subscript>50</subscript> of 0.055 μM and K <subscript>i</subscript> = 0.0225 μM (irreversible inhibition). Beyond these findings, it was concluded that position C-6α is better to functionalize than C-7α, except when there is a C-4 substituent simultaneously. In addition, the methyl group was the best substituent, followed by the allyl group and next by the hydroxyl group. To rationalize the structure-activity relationship of the best inhibitor 13, molecular modeling studies were carried out.

Details

Language :
English
ISSN :
1520-4804
Volume :
62
Issue :
7
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
30852901
Full Text :
https://doi.org/10.1021/acs.jmedchem.9b00157