Synthesis and biochemical studies of 17-substituted androst-3-enes and 3,4-epoxyandrostanes as aromatase inhibitors.
A series of 5alpha-androst-3-enes and 3alpha,4alpha-epoxy-5alpha-androstanes were synthesized and tested for their abilities to inhibit aromatase in human placental microsomes. In these series the original C-17 carbonyl group was replaced by hydroxyl, acetyl and hydroxyimine groups. Inhibition kinetic analysis on the most potent steroid of these series revealed that it inhibits the enzyme in a competitive manner (IC(50)=6.5 microM). The achieved data pointed out the importance of the C-17 carbonyl group in the D-ring of the studied steroids as a structural feature required to reach maximum aromatase inhibitory activity. Further, at least one carbonyl group (C-3 or C-17) seems to be essential to effective aromatase inhibition.
Cepa
Margarida M D S
MM
Biochemistry Laboratory, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha 164, 4099-030 Porto, Portugal.
Tavares da Silva
Elisiário J
EJ
Correia-da-Silva
Georgina
G
Roleira
Fernanda M F
FM
Teixeira
Natércia A A
NA
D000736:Androstenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001141:Aromatase / Q000737:chemistry / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D013329:Structure-Activity Relationship
D000736:Androstenes; D047072:Aromatase Inhibitors; D001141:Aromatase