A Comparison of the Molecular Structures of Six Corticosteroids

A comparison of the molecular conformations of cortisol, 6α-fluorocortisol, 9α-fluorocortisol, and 6α-methylprednisolone, as determined by X-ray analysis, is relevant for purposes of relating conformational differences and biological activity. In 9α-fluorocortisol, the A ring is bent underneath the plane of the molecule to a much greater extent than it is in cortisol, and this bend, which may result from a close nonbonded contact between the fluorine atom and the axial substituent on C(l), resembles the conformational change occasioned by 1–2 dehydrogenation. A correlation was noted between the degree of bowing toward the a face and the variation in antiinflammatory activity in this series of corticosteroids. In all six corticoids for which the 17β side chains were compared, atoms O(20) and O(21) are cis coplanar, and O(20) is oriented over the D ring as predicted by Wellman and Djerassi from solution spectral analysis. Intramolecular hydrogen bonding to the 17α-hydroxyl group is not observed, and intramolecular hydrogen bonding within the side chain, if any, is weak and of highly distorted geometry. Although the 17β side-chain conformation seems nearly invariant, a slight variation is observed in 6α-fluorocortisol which is the only structure in which O(20) is involved in a hydrogen bond.