Comparative AM1 study of the electronic structure of etiocholanes

Abstract

Etiocholanes are metabolites of androstenedione (4-androsten-3,17-dione) and testosterone (17β-hydroxy-4-androsten-3-one). These compounds are produced by the action of 5-reductases which break the π double bond of the androstenes at C4 and C5. The most important etiocholanes are 5β-androstanedione (etiocholanedione), 3α-hydroxy-5β-androstan-17-one (etiocholanolone), 3β-hydroxy-5β-androstan-17-one (epietiocholanolone), and 17β-hydroxy-5β-androstan-3-one (5β-dihydrotestosterone; 5βDHT). Among their most important biological effects are depression of the central nervous system, relaxation of smooth muscle, and stimulation of sexual behavior. The intent of the present study is a determination of the effects of carbonyl and hydroxyl groups at C3 and C17 on the electronic structure of these androgens, in an attempt to gain some insight into their biological action. All calculations were of the semiempirical AM1 type. The decrease of enthalpy caused by an hydroxyl group was found to be twice that of a carbonyl group. The effect of two groups was found to be additive. Carbonyl groups on the other hand led to an increase of dipole moment and of the electrostatic charges on neighboring carbons that were higher than those produced by hydroxyl groups. Carbonyl groups at C17 pushed the highest occupied molecular orbital (HOMO) to higher energy whereas a carbonyl at C3 had little or no effect. However, in mono and di-keto structures, both HOMO and lowest unoccupied molecular orbital (LUMO) were located as expected closer to the carbonyl group. Etiocholanedione, a diketo structure, showed degeneracy of frontier orbitals with its related HOMO−1 and LUMO+1. Structures with mono-hydroxyl or di-hydroxyl functional groups showed the lowest HOMO values; the highest LUMO values and quasi degeneracy of HOMO−1 and LUMO+1. The HOMO and LUMO of etiocholane and for the mono and di-hydroxyl structures were observed diffused throughout the molecules in a “sausagelike” or “ribbonlike” fashion. These results might explain some metabolic steps. Likewise, the difference of intermolecular forces, i.e., dipole moments and charges displayed by the carbonyl and hydroxyl groups, might help to elucidate some biological effects. © 1997 John Wiley & Sons, Inc. Int J Quant Chem 64: 249–254, 1997