Correlation of glucocorticoid and progestational activity with steric, electronic and hydrophobic parameters

In this work an attempt is made to explain the effect of activity enhancing groups in steroids in terms of their physico-chemical effects on the parent molecule. The following equation was derived to correlate the activities of 9α-substituted cortisol derivatives: Log A = 0.07 + 0.76π - 0.22 log P_E + 2.786¹. We found through X-ray crystallographic studies and CNDO/2 calculations that the conformation and electron distribution of the 9α-substituted cortisol derivatives is markedly affected by the nature of the 9α-substituent. These results were correlated with the extent of binding of the steroid to the rat hepatoma cell glucocorticoid receptor. In related work, the progestational activity of 6-substituted-16-methylene-17α-hydroxy-4,6-pregnadiene-3, 20 diacetate derivatives was correlated equally well by the equations: Log A = 0.17 + 1.06π = 3.46F - 10.5π² or Log A = 0.26 - 0.07MR + 0.97π + 2.84F.