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
The study of the relationship between steroids and certain fatty acids led us to the hypothesis, according to which some steroids are derived from fatty acids themselves. Although the synthesis of cholesterol from scalene (230) is highly plausible, it would not represent the only origin for all the steroids. The members with a two carbon chain would derive from other substances. We present this hypothesis here because it also represents an example of another important role played by the double bonds which appear to intervene in the process of cyclization in the organism.
According to the hypothesis which we have advanced, polyunsaturated fatty acids lead to allopregnane, the parent steroid with a two carbon lateral chain. Figure 255 shows the different phases of such a transformation starting from arachidonic acid. The presence of a carboxyl and four double bonds in the arachidonic acid molecule results in some of its carbons having a particularly strong energetic value. The strongly charged carbons are: 1) C1, through its bond to = O and — OH; 2) C2 and C3, through an induction process since they are close to the carboxyl; and 3) C5 and C0, C8 and C9, C12 and Ci3, and Ci0 and C17, respectively bound by double bonds.
Due to alternate induction, all the odd numbered carbons have a positive sign and the even numbered have a negative one, as indicated in Figure 255a. Because of the high flexibility of the aliphatic chain, and the presence of carbons with strong positive and negative character in the same molecule, attractions between the strongly charged carbons with opposite electrical signs in the same molecule would occur. This would lead, as a first step, to a bending of the chain so that the strongly charged carbons with opposite signs would face one another. (Fig. 255b)
In a second step, as these carbons are bound by double bonds, the respective π electrons of the double bonds would serve to form a new bond between the facing carbons and thus to close cycles. This would occur without any loss or gain of electrons. The three double bonds between C5 and C6, C11 and C12, and C14 and C15 would serve to close the three cycles. (Fig. 255c) The double bond between C8 and C9 would serve to make C9 highly reactive. It can be seen that C9 of arachidonic acid corresponds to C3 of cyclopentanophenanthrene, which explains why this carbon has a high positive character, with an oxygen fixed on it. The carbon of the car boxyl could be used either to form the methyl group at C13 or, more plausibly, could be lost in a process of decarboxylation, which by itself, in this case, would induce the bond between C2 and C18 of the arachidonic molecule. Through the intervention of the strong energetic center, the pentanic cycle would be closed and would have two carbons with the same charge. (Fig. 255d) The two methyls, corresponding to C18 and C19 of steroid molecules, would result from a further process of methylation after the polycyclic molecule was formed. C2 and C6 of arachidonic acid would be especially likely to have a methyl group fixed on them through their electronic displacement due to the new bond.
Fig. 255. Hypothesis of the synthesis of the allopregnane radical from arachidonic acid. Fig. (a) shows the relative position of the double bonds in the arachidonic acid molecule. Fig. (b) shows how the molecule bends, due to the attraction between the energetically oppositely charged Ca and C2, C5and C14, and C6 and C11. In Fig. (c) the cycles are closed with the electrons furnished by the double bonds, (d) The closing of the cyclopentane occurs with the appearance of a twin formation. The electrons of the double bond between C8 and C9 become available at C9 (C3 of allopregnan) to realize the bond with an oxygen at this carbon.
This hypothesis explains the biological relationship between arachidonic acid and corticoids. The adrenals are especially rich in both. The synthesis, which occurs with a minimum change in the richness in electrons or atoms, explains two of the most important characteristics of these corticoids, the high energetic value of C3 and of the cyclopentane with its twin formation. Preliminary experiments seem to show that, in a preparation of adrenal tissue, arachidonic acid can be transformed to corticoids under the influence of the adrenocorticotrophic hormone of the hypophysis (ACTH).
Through reciprocal influence, the energetic centers present in the non polar parts of two molecules which combine, largely lose their activity. Steric coupling is possible if the two opposite molecules, once bound through the combination of their polar groups, also adhere together through their nonpolar groups via the opposing energetic centers or formations present in the two molecules. In this way, steric coupling completes the partial reciprocal neutralization of the molecules obtained through the combination of polar groups. The bond between the polar groups that keeps the two molecules in a reciprocal position is thus an important condition for steric coupling.