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
Among the most important steroids are those having a two carbon chain fixed at C17.
Two groups, the luteoids and corticoids, appear directly related to allopregnane hydrocarbon, the steroid polycycle with a two carbon lateral chain fixed at C17. As we have already seen in the hypothesis concerning the origin of the steroids (Note 11), this hydrocarbon could have been directly derived from arachidonic acid, the two carbon lateral chain corresponding to the tail chain of this acid, a tail which remains after cyclization.
The prototype of the luteoids is progesterone. Two polar groups C = O are present, one at C3 of the polycycle and the other at C20 of the tail chain. A parallel double bond between C4 and C5 completes the formula. Energetically, progesterone presents a first center at C3 which appears strongly nucleophilic for two reasons: first, because it corresponds to the potent electronegative C3 and second, because it is reinforced by a double bond present between C, and C5, and which is hence parallel with the double bond of the carbonyl. The second = O is attached to the C20 of the tail chain. This also appears reinforced, the double bond of this carbonyl being parallel to the bond between the C13 and C17, which in the cyclopentane, according to the hypothesis of twin carbons, binds two negative charged carbons. Through its constitution progesterone is also a lipoid, the complex hydrocarbon group being predominant over the polar groups. With its polar nucleophilic centers, progesterone has the fundamental character of acid lipoids. Progesterone's luteoid activity corresponds to the presence of two relatively strong neutrophilic centers kept in the characteristic positions, one at C3 and the other at C20.
We can see that any disturbance in this energetic picture, any change from the dinucleophilic at any center, decreases the luteoid properties of the substance. With more profound changes, the luteoid activity is even suppressed. (Note 13)
The corticoids represent the group of hormones upon which the attention of scientists recently has been intensively focused because of their new therapeutic applications.
Chemically, they appear to be the same as luteoids, derivatives of the same parent hydrocarbon, allopregnane. Structurally, all these adrenocorti coid hormones have: a) a C3 binding an O group; b) a double bond between C4 and C5 in the first cycle; c) a two carbon tail chain with an O attached in ketone form to C20; d) an OH as primary alcohol present at C21. This structure, common to all corticoids, seems to be responsible for the principal properties of these substances. Corticoids have been separated into subgroups based upon the presence of attached groups OH or = O at C11 or OH at C17. The presence or absence of attached radicals at C11 appears to be most important. Corticoids without attached radicals at the C11 have a major influence on the metabolism of electrolytes. The second group of corticoids, having the radical, are known as neoglucogenic corticoids, the name indicating their principal biological characteristics.
Energetically, the corticoids present a nucleophilic center at C3, reinforced by the presence of the double bond in the cycle between C4 and C5. The double bond is parallel to the double bond of the carboxyl, and thus inductively increases the ionic character of the latter.
A second energetic group of the tail chain appears in toto as a strong tripolar center with a nucleophilic center at C20 of this chain and an electro philic center at C21. (Note 14) To this basic pattern is added, in the neoglucogenic corticoid, a separate energetic center at C11, which can be either electrophilic, formed by a hydroxyl, or nucleophilic, formed by an oxygen.
Corticoids appear, in general, to act as positive lipoids. (Note 15) Because of their importance in relation to anti fatty acid activity, we will discuss first the neoglucogenic corticoids, the members with a polar group also at C11- According to our hypothesis, these steroids have a special biological activity, a role in the process of synthesis in the organism. The part of the molecule between C11 and C21 constitutes an energetic formation with a peculiar property. It represents a kind of energetic mold or template, in which each carbon has its specific energetic character. Different radicals would be attracted by the energetic centers of this template formation according to their own energetic nature. Kept in their respective positions, they would be induced to bind together in order to form new substances. In this manner this template formation would promote new syntheses. In different corticoids the constitution of the C11 =C21 formation will differ and this will determine which substance is to be synthesized by the respective mold or template formation. (Note 16)
Using the template hypothesis, we studied an entire series of body constituents forming the "gluco group." Glucose, galactose, glucosamine and galactosamine, with their respective acids, as well as ascorbic acid, are among theses substances. According to our hypothesis, these neoglucogenic corticoids would have the important role of producing, possibly along with other mechanisms, the entire series of "gluco" constituents. The existence of different template formations would result in a variety of synthesized constituents.
The intervention of the template formation in synthesis can occur again and again without affecting the molecule of the corticoid as such. It is interesting to note here a structural curiosity which could be interpreted as being related to template activity. In this template, the group of successive C11, C12, C13 and C17 are part of the rigid skeleton of the cyclic molecule, while C20 and C21 are forming the lateral chain attached to C17. This can be regarded as conferring a certain proper mobility to this lateral chain as related to the polycycle. It is conceivable that this lateral chain would become a closed formation when synthesis takes place. A movement of the chain at C17 would permit the mold to open and thus liberate the synthesized molecule. It is interesting to note here the importance of the structure of the template for the constitution of the substances synthesized. Besides the polar group at C17, that at C11 is also important for neoglucogenic activity since it insures a six carbon chain in the synthesized molecules. A hydroxyl or carboxyl at the C6 of the synthesized substance will appear, according to the nature of the polar group at C11 of the steroid. The respective characters and positions of C21 and C12 will permit the appearance of a cycle formed by five carbons and an oxygen, characteristic for the pyranic form of newly synthesized substances.
An interesting confirmation of the template hypothesis was obtained when glucosamine which, according to the hypothesis, is synthesized by the cortisone molecule, was found to induce in patients many of the clinical changes which are obtained by treatment with cortisone. We will consider these results later in our discussion of therapy. The capital role played by glucosamine, galactosamine and the respective uronic acids in the constitution of the connective tissue represents the "missing link" for the explanation of the relationship between cortisone, the other neoglucogenic corticoids, and this tissue. Some part of the therapeutic effect obtained with these neoglucogenic corticoids in diseases of the connective tissue has to be attributed to the intervention of the amino sugars.
In the study of anti fatty acid activity, glycerol and glycerophosphoric ion were found to control the absorption and circulation of saturated mono-, di-, or tri unsaturated free fatty acids. The sterols appear to counterbalance the normal polyunsaturated members while adrenal corticoids, and especially the neoglucogenic corticoids, counteract the toxicity of fatty acids in general and of the abnormal conjugated members in particular. Research done in our laboratories by E. F. Taskier indicates that the adrenals intervene in the defense mechanism against fatty acids, and especially against the conjugated members which appear to be related to abnormal conditions. (Note 17)
The part of our research concerned with the role of lipoids in normal and abnormal physiology has been almost entirely guided by the concept of an antagonism between the two groups, one with a positive and the other with a negative polar character. This specific aspect has led us to study, together with the fatty acids and the anti fatty acids, other substances related to this antagonism. In the group of lipoacids or acidic lipoids, as obtained from tissues, organs or organisms, we recognized the group of porphyrinic acids, related to various hemes present in the organisms. In the group of anti fatty acids obtained from the same sources, different constituents form the insaponifiable fractions.
As related to this dualistic aspect we have studied another group of substances, which appear to act in the organism against the anti fatty acids themselves. These other substances would represent a kind of biological brake to counteract an exaggerated intervention of anti fatty acid constituents.
We have made a special investigation of two substances of this group, glucuronic and sulfuric acid anions, which characteristically seem to oppose certain anti fatty acid substances. These substances appear as a result of an exaggerated oxidation of normal metabolites. Under abnormal conditions, the oxygen resulting from the intervention of peroxide may be fixed to carbohydrates even before they have undergone the preliminary fermentative transformations seen in normal metabolism. With the aldehyde group bound to phosphoric acid, the oxidation takes place at C6, the second most reactive carbon in the molecule. This direct oxidation would represent, according to our view, one of the sources of glucuronic acid. Similarly the sulfuric anion would result from the oxidation of sulfur present in the organism. They correspond to the oxygen phase of offbalance D.