This section is from the book "Research In Physiopathology As Basis Of Guided Chemotherapy With Special Application To Cancer", by Emanuel Revici. Also available from amazon: Research In Physiopathology
It appears that the luteoid pattern can be correlated to a specific aspect of the energetic picture of this substance—the presence of two relatively strong nucleophilic centers in the characteristic opposite positions, one at C3 and the other at C20, as in progesterone. In fact, any change in the energetic picture of this steroid will decrease luteoid properties. The relationship of the luteoid property to the nucleophily at C3 is easily seen. The lack of the nucleophilic center at the carbon 3, as in pregnane one 20, (Fig. 256a) leads to an inactive substance, the energetic picture being entirely changed. A single nucleophilic center thus appears to be insufficient for the luteoid property.
The substance becomes inactive if, instead of a nucleophilic center through = O at the carbon 3, an electrophilic center is present, as in the pregnane ol 3 one 20, so that the energetic picture no longer corresponds to the luteoid pattern. (Fig. 256b)
Any change in the nucleophily of the C = O center at C3 will decrease the luteoid properties of the substance. The presence of a second double bond between carbons 6 and 7, as in the 4, 6 pregnandiene dione 3-20, (Fig. 256c) in spite of the fact that it will increase the value of the nucleophily of the carbonyl at the carbon 3, will change the energetic pattern and thus also decrease the luteoid character. On the other hand, the reduction of the nucleophily of the center produces, through a similar influence upon the energetic pattern, a decrease in the luteoid property. In the case of pregnane trione 3-6-20, (Fig. 256d) the lack of a double bond in the cycle and the reciprocal induction realized by the parallel double bonds of the two carbonyl, will reduce the nucleophily of the C3 center, and with it, the luteoid properties. This also is true for Δ 5 pregnene dione-3-20-ol 6, (Fig. 256e) where the presence of the hydroxyl at the C6, as well as a nonparallel double bond between C5 and C6, decreases the ionic character of the C = O at the carbon 3. In A 5 pregnene dione 3-20, (Fig. 256f) where only the double bond between carbons 5 and 6 is changed, being opposite to that of the carbonyl at the carbon 3, the ionic value of C = O at C3 is decreased instead of increased. The luteoid property seems to have almost disappeared.
The second condition for the luteoid property is the nucleophilic center at C20 Any change in its character or value will influence the luteoid property of the substance. Androstandione, (Fig. 256g) with a nucleophilic center at carbon 3 similar to that of progesterone, but with an = O directly attached to carbon 17 and without any side chain, presents an energetic picture with two nucleophilic centers. But the nucleophilic center = O attached directly at carbon 17, gives a different character to this part of the molecule. The substance thus has only some luteoid properties. A 4 preg nene one 3-ol-20, (Fig. 256h) in which the carbonyl at carbon 20 is changed by a hydroxyl, is, on the other hand, inactive, the substance having a picture different from that of the dinucleophilic pattern. Also inactive is Δ 5 pregnone—dione-3-20-ol 17, (Fig. 256i) in which the presence of the hydroxyl at carbon 17 changes the energetic picture at this extremity of the steroid.
Fig. 2S6. Any change in the energetic characteristics of the centers which appear related to the specific luteoid activity leads to a decrease or disappearance of this activity.
The presence of a double bond between carbons 11 and 12 (Fig. 256j) will decrease luteoid activity through an induction and field influence between the nonparallel double bonds and a decrease of the ionic character of C20 bound to oxygen. The influence exerted by an hydroxyl in the neighborhood of carbon 17 is interesting. Through an inductive effect, the OH attached at carbon 12 (Fig. 256k) changes the ionic value of the C = O attached at carbon 20 and thus decreases luteoid activity. An hydroxyl bond to carbon 11 has a much more intensive effect, changing the ionic character of the bonds between it and the = O and thus inactivating the luteoid property. (Fig. 2561)
For most of the steroids with = O centers, metabolism leads to a change of this center in an hydroxyl. The product of the change of both C = O into C = OH, which represents the form in which this hormone is excreted, is inactive. Pregnane diol 3-20, (Fig. 256m) with a structure far removed from the pattern required for luteoid activity, has no luteoid properties.
Energetically, as a consequence of the presence of a nucleophilic center in this situation, there is a strong positive charge for the carbon 20 of the chain itself. Consequently, a strong negative charge appears for carbon 21. The ionic value of the bond linking OH to C21 is thus increased. With the reactivity of this radical increased, the electrophilic character of this OH center becomes still stronger. The respective activity of two opposed energetic centers near to each other is increased inductively.