Theoretical Investigations on the Role of Steroid-Skeleton C4 = C5 Unsaturation in Competitive Aromatase Inhibition

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Abstract
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 5a-androstane- 3,17-dione is applied to give indications about the role of the C 4 = C5 double bond in competitive inhibition of human placental aromatase and about sterical requirements in steroidaromatase interactions. The inhibitory activity is found to correlate with the sterical MTD variable, hydrophobicity, and π-system conjugation in the A,B-ring region. A comparison of the MTD results reveals a good agreement with interpretations based on freeenergy 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 enzym atic transformations. While 19-hydroxy-5a-androstane-3,17-dione favour a conformation having the hydroxyl group in the enzyme-directed out-of-ring position, the C 4 = 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 π conjugation.

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