Austin Model 1 study of the effect of carbonyl and hydroxyl functional groups on the electronic structure of androstane

Abstract

Androgens are steroid hormones with a wide variety of biological actions. Biochemically, testosterone the main hormone is reduced at C5 yielding 5α and 5β-reduced androgens. Frequently, those 5-reduced androgens show biological actions different to testosterone. Besides, these compounds have either carbonyl and/or hydroxyl groups placed at carbons 3 and 17. The present work was aimed to explore the importance of such functional groups in 5α-androstane. Carbonyl or hydroxyl groups alone or combined at C3 and C17 were systematically included to 5α-androstane resulting a set of 16 different structures. The electronic structure of the 16 structures was studied using the Austin Model 1 (AM1) semi-empirical method. The results showed, that hydroxyl groups decreased the enthalpy of formation of 5α-androstane almost two-fold than carbonyl groups. Higher energy values for the HOMO and lower energy values for the LUMO were observed in structures bearing carbonyl groups. The 3-D picture of the HOMO and LUMO for the template (5α-androstane) as well as the mono- and di-hydroxy substituted structures were observed widespread along the molecules in a ‘sausage-like’ or ‘ribbon-like’ fashion. However mono- and di-keto-substituted structures showed that both HOMO and LUMO were located closer to the carbonyl groups. Carbonyl-substituted structures showed also the higher dipole moments and higher electrostatic charges. The lower values of enthalpy, dipole moments and electrostatic charges of hydroxylated molecules suggest a higher stability and lower reactivity of these compounds. Moreover, keto and di-keto structures which have the frontier orbitals at the neighborhood of these groups might facilitate a nucleophilic attack at the HOMO. It may be concluded that carbonyl groups increase the intermolecular forces of androstanes enhancing the probability to exert a biological action. Likewise, the metabolism of androstanes might be facilitated by the presence of carbonyl groups.