New analogous progesterone haptens and their A/B ring conformation: Determination of dihedral angles using extended Karplus equations

Abstract

The specificity of progesterone action largely depends on the conformation of its ring A in solution. Selectivity and specificity dr haptens for Immunoassay is dependent on their conformational similarity to that of the parent molecule. Conformational distortions due to bully substituents have often led to a loss in activity. Therefore, determination of conformation of the steroidal rings has always been an area of high intrinsic interest. Conformational analysis of the A/B rings of the synthesized steroid hormone derivatives, viz. 16 alpha-methylprogesterone, 6 beta-hydroxy-16 alpha-methylprogesterone, 16 alpha-methylpregn-4-en-3,6,20-trione, 16 alpha-ethylprogestrone, 6 beta-hydroxy-16 alpha-ethylprogesterone, 16 alpha-ethylpregn-4-3n-3,6.20-trione, 16 alpha-prop-2'-enylprogesterone, 6 beta-hydroxy-16 alpha-prop-2'-enylprogesterone, 16 alpha-prop-2'-enylpregn-4-en-3,6,20-trione has been carried out using high resolution ID proton NMR spectra. Calculations are carried out by employing three of the latest extensions to the Karplus equations, viz those suggested by Colucci, Osawa and Barfield. The A ring conformations of these steroids are determined by calculating dihedral angles of the ethane fragments consisting of C1-C2 and C6-C7 from the vicinal coupling constants derived from high field H-1 NMR spectra of the hormone derivatives. The dihedral angle theta could not be calculated directly since the nature of the equations is not truly quadratic. A program has been devised wherein the calculated J value has to be fitted to the observed J value for each of the Colucci, Osawa and Barfield equations, Molecular modeling of the 4-en-3-one steroid hormone derivatives has also been carried oat using MM2 calculations.