Comparative study of the electronic structure of estradiol, epiestradiol and estrone by ab initio theory

Abstract

Estradiol (1,3,5 (10)-estratriene-3,17-diol), epiestradiol (1,3,5 (10)-estratriene-3,17-diol), and estrone (3-hydroxy-1,3,5 (10)-estratrien-17-one) were studied by ab initio quantum mechanics theory. The Hartree–Fock method and the 6-31G* basis set, were used to assess precise geometries, electronic structure and related physicochemical properties. The selected estrogens are different only by the position, or the quality of the functional group at C17. However, their biological actions change importantly, justifying a comparative study. Additionally, X-ray crystallography data of the estrogens were submitted to single point calculation at the ab initio level with the 6-31G* basis set. The results of crystal conformers were compared with the ab initio theoretical values. Bond distances and valence angles were quite similar in all the cases, however, measurement of the root-mean-square differences of the steroid nucleus and dihedral angles showed some variations among estrogens. Important differences were also observed in hydroxyl and carbonyl functional groups. Geometrical differences correlated with molecular differences of total energy, HOMO and LUMO values, dipole moments and electrostatic potentials position. In all the steroids studied the HOMO, LUMO and a big electrostatic potential were located at the A-ring. In estrone the carbonyl group at C17 elicited a different and larger electrostatic potential than that elicited by the hydroxyl group in estradiol and epiestradiol. It is concluded that similarities in A-ring electrostatic potentials and electronic densities of estradiol, epiestradiol and estrone might explain similar non-genomic effects such as smooth muscle relaxation, neurotransmitter release, antioxidant effect and estrogen receptor recognition. Likewise, differences at C17 functional groups might explain differences in the genomic action of estrogens.