Ab initio comparative study of the electronic structure of testosterone, epitestosterone and androstenedione

The geometries and electronic structure of testosterone (T), epitestosterone (E) and androstenedione (A) were assessed at high ab initio level, using the 6-31 G* basis set. These androgens are related chemically, changing only one functional group, i.e. 17 beta-OH (T), 17 alpha-OH (E), or 17-keto (A), but with different biological activity. Bond distances, valence angles and torsional angles were measured. In addition, total energy, Valence orbitals, i.e. highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), electrostatic charges, dipole moment and electrostatic potentials were measured. Rotation barriers of the 17-OH functional group were also explored for T and E. Geometries showed good agreement with X-ray crystallography structures, except for some dihedral angles of the D-ring. Results showed high electronic density surfaces at C17, according with the stereochemical arrangement of the functional groups and the electrostatic potentials emerging from the lone pair electrons of the oxygens. HOMO and LUMO were located at the A-ring of the steroids, between C4 and C5 included in a high electronic density produced by the pi electron delocalization along the O3=C3-C4=C5 conjugation. These findings increase the feasibility of a chemical reaction at this point, explaining the metabolism of these androgens toward 5 alpha and 5 beta derivatives. The dipole moment vector was observed traversing the molecules from the C3 carbonyl toward the C17 in T and E, changing slightly in androstenedione. The rotation barriers of the C17-OH group showed the interaction among geometry, enthalpy, electronic charge density, dipole moment and orbital energies. All of these features might explain to some extent the metabolism of androgens and the qualitatively different intermolecular forces at C17 which change the affinity for receptors and the biological actions. (C) 1998 Elsevier Science B.V.