Theoretical investigations on the role of steroid-skeleton C4 = C5 unsaturation in competitive aromatase inhibition.
A quantitative structure-activity relationship (QSAR) approach by use of the minimal topological difference (MTD) method including 46 derivatives of 4-androstene-3,17-dione and 5 alpha-androstane-3,17-dione is applied to give indications about the role of the C4 = C5 double bond in competitive inhibition of human placental aromatase and about sterical requirements in steroid-aromatase interactions. The inhibitory activity is found to correlate with the sterical MTD variable, hydrophobicity, and pi-system conjugation in the A,B-ring region. A comparison of the MTD results reveals a good agreement with interpretations based on free-energy data derived from inhibition constants. By means of MM2 molecular mechanics and PCILO quantum-chemical calculations, the 4-ene structure is shown to significantly influence conformational features of C19 substituents which are important in enzymatic transformations. While 19-hydroxy-5 alpha-androstane-3,17-dione favour a conformation having the hydroxyl group in the enzyme-directed out-of-ring position, the C4 = C5 double bond energetically enables the steroid to adopt a conformation which can be hydroxylated without internal rotations. According to present theoretical findings, the 4-ene unsaturation thus exerts an indirect conformational influence by hydroxyl positioning appropriate to aromatase interactions and a direct electronic influence by pi conjugation.
Bohl
M
M
Akademie der Wissenschaften der DDR, Zentralinstitut für Mikrobiologie und experimentelle Therapie, Jena.
Simon
Z
Z
Lochmann
J R
JR
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology*; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D005043:Etiocholanolone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D047072:Aromatase Inhibitors; D000735:Androstenedione; C006576:androstane-3,17-dione; D005043:Etiocholanolone