We have considered the existence and importance of these "twin formations" as indications of energetic activity in the course of studies on electronic molecular arrangements. In a molecule, an alternation of successive atoms results in part from the alternating polarity of these atoms within a molecule and in part from the opposite characters conferred upon the two carbon atoms when they form acetic acid, an important precursor in biological syntheses. It is through alternate polarity that an induction effect of an energetic center in the molecule propagates itself along the chain. The presence of any energetic center in the molecule represented by polar groups or a lateral chain, for instance, will enhance this alternate polarity. When one or more such inductive effects are propagated through the chain, two adjacent atoms may be found to possess the same electrical sign for their charge or ionoid character. The twin formation which results represents a center of increased molecular reactivity. This reactivity can be so intense as to lead to breaking down of the molecule, something which occurs often in inorganic substances. This has led Pauling to believe that this condition, called "adjacent charge rule," cannot exist.

"Pauling has pointed out that the mutual potential energy of two electrical charges of the same sign is so high that a canonical structure having net residual charges of the same sign on any adjacent atoms would have too high an energy level to contribute appreciably to the real molecular structure." So notes William A. Waters in "Physical Aspects of Organic Chemistry." (45)

The form suggested for nitrogen peroxide (N2O4), (Fig. 96) would appear to be impossible because of the high energy developed at the two positive nitrogens.

Nitrogen Peroxide

Nitrogen Peroxide

Fig. 96. The existence of nitrogen peroxide molecule is prevented by the high energy developed at the two adjacent positive nitrogens.

However, the forces that exist in most of the organic molecules are much weaker, so that the resulting "twin formations," although energetically potent, are not strong enough to induce the breaking down of the molecule. Consequently, they would exist and represent important energetic centers.

We have studied a number of carcinogenic agents, seeking twin formations. Analysis of the ionoid character of the carbons of the methylcholan threne molecule reveals the presence of twin formations which could be localized at various points of the molecule. Figure 97 shows the energetic aspect of methylcholanthrene and the ionoid character of its carbons. It is the presence of the cyclopentane group in the molecule that induces the same sign in two adjacent carbons. The presence of the methyl group would determine the electrical character of C20 and consequently the succession of alternate signs. On the other hand, the double bonds will determine the probable localization of these twin formations in the molecule at the K formation itself, that is, at C5 and C6.

Methylcholanthrene

20-Methylcholanthrene

Fig. 97. The energetic aspect of methylcholanthrene, with twin formations.

Twin formations can be found in many carcinogens. It must be emphasized, however, that unequal energetic values can be recognized easily for different twin formations and would explain differences in their activity, a fact which would confer possible plural properties upon this group of qualitatively similar energetic formations.

Another aspect of the relationship between these formations and carcinogenesis appears to be even more interesting. While no twin formations can be found in several agents, the formations are present in the substances resulting from metabolism of these agents in the body. The relationship of twin formation to carcinogenic activity can be suspected when such changes appear simultaneously with carcinogenicity.

For example, no twin formation occurs in 2-naphthylamine, (Fig. 98) whose direct carcinogenicity is questioned, but such a formation appears in heterocyclic 3:4:5:6 dibenzcarbazole, one of its intermediates (46), which is known for its carcinogenic properties. (Fig. 98bis) This is also true for aminofluorene, which is also related to 2-naphthylamine. (Fig. 99) The existence of a twin positive carbon group or a twin negative in the same molecule can further explain the diversity of the tumors produced by this carcinogen and its acetyl derivative, which has the same energetic picture. (47, 48, 49, 50, 51, 52)

2 Naphtylamine

(a)

2-Naphtylamine

Fig. 98. No twin formations exist in 2-naphthyIamine.

3:4:5:6 Dibenzcarbazole

(b)

3:4:5:6 Dibenzcarbazole

Fig. 98bis. A twin formation appears in the intermediate 3:4:5:6 dibenzcarbazole.

Twin carbons can be correlated with the degree of carcinogenicity of the sulfur isosters (53) in each of which a thiophene nucleus replaces the benzene ring of 9:10 dimethyl 1:2 benzanthracene. This also applies to the azo compounds with twin formation at the level of the azo bond. Figure 100 shows the presence of a twin nitrogen at the level of the azo bond, due to the influence exerted by the symmetric rings.

2 Aminofluorene

2-Aminofluorene

Fig. 99. A twin carbon group is present in aminofluorene.

Furthermore, it is the relationship of twin formation to carcinogenicity which indicates the need for considering the metabolism of various carcinogens in the organism.

Dimethylamino azobenzene, butter yellow, which has a twin formation and is an active carcinogen, can become still more active through the metabolic changes occurring in the body which lead to products with twin carbons. The same 2:2'-azonaphthalene, with a twin formation, becomes more active because of its transformation into amines passing through hydrase compounds. 2:2'-diamino l: l'-dinaphthyl, with twin carbon formation, is more active than the precursor, 2:2 Azonaphthalene. (54), (Figs. 101 and 102)

4   Dimethylamino azobenzene

4 - Dimethylamino azobenzene

Fig. 100. A twin formation is present in 4-dimethylamino azobenzene at the level of the azo bond.

It is possible that benzidine rearrangements of the hydrazo derivative determine twin formation and thus explain its carcinogeneity.

The similarity in kinds of tumors produced by the derivatives of 4-aminostilbene (Fig. 103), and the aminofluorene derivatives (55), makes us think that twin formations can appear in this case through changes occurring in the organism.

2:2' Azonaphthalene

2:2' Azonaphthalene

Fig. 101. 2:2'Azonaphthalene has only a slight activity.

Some artificial estrogens of high potency (56) diethylstilbestrol and triphenylethylenic acid, (57), (Figs. 104 and 105) are known to have carcinogenic activity. While a twin carbon is present in both, such a formation is assumed to appear more active in the latter, as the result of metabolic changes in the body.

Fig. 102. The passage of 2:2' azonaphthalene into the active 2:2'-diamino 1: 1'-di naphthyl results in the appearance of an active twin carbon formation due to the influence exerted by the amino group.

2:2'   Diamino 1:1'   dinanhthyl

2:2' - Diamino 1:1' - dinanhthyl

An interesting aspect is furnished by urethane and other esters of car bamic acid. Figure 106 shows that no twin formations can be seen directly or through a change in the molecule. This accords with these substances' lack of capacity, noted by many authors, to induce cancerous lesions or even tumors. (58, 59, 60) Orr (61) relates lesions produced by carbamic acid esters to chronic inflammations, noting their regression when treatment is discontinued. (Note 1)

From analyses of the substances able to induce invasive cancers, it can be observed that many present a twin carbon or nitrogen formation, usually activated by the induction exerted by a polar group or by double bonds. Some of these substances originally without twin formation become carcinogens only when changes occur in the body leading to the appearance of a twin formation.

4 Dimethylaminostilbene

4-Dimethylaminostilbene

Fig. 103. 4-Aminostilbene derivative.

It must be emphasized, however, that according to the concept of plural factors in carcinogenesis, twin formation does not appear to be an obligatory condition for carcinogenic activity; other factors can produce such activity.

It is interesting to note that in most carcinogens, especially in the hydrocarbons, the twin formation is electrophobic due to its richness in electrons. For the present, we wish to stress only that in substances considered to be actively carcinogenic, i.e., capable of inducing invasive cancer, twin formation appears to be an added factor which insures complex activity. Intervention of groups of two energetic centers with the same character, in carcinogens, places in a special light a group of agents which, under particular circumstances, induce tumors. One group with alkylating activity, is formed by the nitrogen mustards, diepoxides, polyethylene amines and dimethanesulfonoxyalkanes. One of the physicochemical characteristics of this group is the presence of two electrophilic centers near enough to each other to permit joint action. Still more important seems to be the fact that, through changes in all these substances, new formations may appear which energetically could be ultimately considered similar to twin formations. Through this character, their activity could also be parallel to that encountered in the carcinogens mentioned above.

4 Dimethylaminostilbene

4-Dimethylaminostilbene

Fig. 104. A twin formation exists in diethylstilbestrol.

Triphenyl ethylene

Triphenyl ethylene

Fig. 105. The position of the twin formation in triphenyl ethyiene.

Urethan

Urethan

Fig. 106. Urethan has no twin formation and apparently—according to many authors —no direct carcinogenic activity.