Electronic Structure and Carcinogenic Activity

Numerous attempts have been made from manypoints of view, both chemical and physical, to account for the differencesin carcinogenicactivity ofvarious aromatic compounds (6, 7) and, thereby toexplore the riddle of carcinogenesis due to thesesubstances. The experimental approaches includedinvestigations of chemical constitution (926),fluorescence (5), phosphorescence (920),absorptionspectra (16, 17), etc., but no satisfactory explanation has ever been given for the exact nature ofcarcinogenic compounds.

A large majority of the important carcinogensbelong to the aromatic hydrocarbons, aromaticheterocyclics, and aromatic amines, which arecharacterized by having a certain number ofmobile electrons, so-called ir-electrons. 0. Schmidt(927)first attempted to relate the carcinogenicity ofaromatic hydrocarbons with the distribution of7-electrons in these compounds, and thereaftermany physicists and theoretical chemists such asA. and B. Pullman (9292,92.5),Daudel (9), Berthierand Coulson (92),Greenwood (14), and Dewar (10)have endeavored to explain carcinogenicity fromthe nature of ,r-electrons. Among these works thePullmans' “K-regiontheory― (8, 925)appears to bea basis for further study.

The Pullmans carried out the calculations of ther-electron distribution in molecules and developedtheir theory by means of a “moleculardiagrammethod.― Ilowever, this method was not applicable to large molecules on account of the complexities of the calculations. The calculation is toolaborious to make in the case of polycondensedaromatics, i.e., for the molecules with five or morecondensed benzene rings, to which group many p0-tent carcinogens belong. Thus, by the molecular

* This work was aided by a grant from the Ministry of

Education, Japanese Government.

Received for publication August 11, 1954.

diagram method they could give only qualitativeinformation as to these compounds.' Moreover, asBoyland (3) and Kooyman and Heringua (18)pointed out, by considering the K-region alone itseems difficult to explain the mechanism of carcinogenesis. In spite of all the quantum-mechanical approaches attempted, therefore, it has not yetbeen possible to construct a complete theory ofcarcinogenicity by a consideration of the ir-electron system.

Some of the present authors (192, 13) have previously discovered the significance of what we callIrontierekctronsinchemicalreactionsof ir-electronsystems and have succeeded in explaining the ex

perimental results satisfactorily by means of calculating the frontier electron density. Furthermore, it has been found that a distinct parallelismexists between carcinogenicity and the frontierelectron distributions. In the present paper the relation between the calculated frontier electron distributions and carcinogenicities of nonsubstitutedaromatic hydrocarbons is reported, and at thesame time some discussions are given about the

activity of carcinogens. The results on substitutedaromatic hydrocarbons, aromatic heterocyclics,and aromatic amines will be reported in the nearfuture.

OUTLINE OF TREORETICALTREATMENTS

All the compounds which the present papertreats belong to the ir-electron system. It is wellknown that w-electrons are very mobile and would

be considerably influenced by outer disturbances.Consequently, absorption spectra, magnetic anisotropy, chemical reactivity, and many otherphysical and chemical properties which are charac

‘Under these circumstances the Pullmans used in theirrecent papers (23, 24) the localization method, of which mention is made in the next section.

9233

of Aromatic Compounds

I. Condensed Aromatic Hydrocarbons*

CHIIc@YosHI NAGATA, KENICHI FUKUI, TEIJIR0 YONEZAWA,

AND YUSAKiJ TAGASHIRA

(Departments of Fuel Chemistry and of Pathology, Kyoto University, Kyoto, Japan)

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Cancer Research9234

teristic of the w-electron system are ascribed toir-electrons.

Two methods exist in the quantum-mechanicaltreatment of ir-electron systems. One is the “va-,lence bond (V.B.) method― and the other is the“molecular orbital (M.O.) method.― Because ofthe excessive tediousness of the exact yB. treatment for large molecules, several approximatemethods have been developed. They involve, however, a considerable amount of arbitrariness whichmakes the results doubtful. On the other hand, theMO. method has proved to be more readily applicable to large aromatic molecules such as the carcinogenic compounds. Under these circumstancesmost of the chemical and physical treatments ofir-electron systems are based on the M.O. method.

The discussion of chemical reactivity of ther-electron system has been made through two different ways of approach in the M.O. theory. Thefirst is called “localization method― of Wheland(31). In this method, it is assumed that the rate ofreaction at a certain position in a molecule is determined by the “localizationenergy― which is required in localizing a requisite number of ir-electrons at that position. The second is called the“staticmethod.―2 In this method the chemical reactivity at a position in a molecule is correlatedwith the density of all the w-electrons at that position in the isolated molecule.

The fundamental supposition in the localizationmethod is that a parallelism would exist betweenthe localization energy and the chemical reactivity. On the other hand, the basis of the static method may be valid when the interaction between themolecule and the reagent is very small. In both ofthe two methods mentioned above, the chemicalfeature of the process of reaction is not directlyconsidered. Namely, in these methods the mechanism of formation and dissociation of cr-bonds isnot taken into consideration. Accordingly, thesetwo methods are not considered to be sufficientlysatisfactory to describe the true process of chemical reaction.

Frontier ekctron method.—Someof the presentauthors introduced the frontier electron method asa third one of molecular orbital treatments ofchemical reactivity (11—13). In that theory theelectronic interaction between the molecule andthe reagent has been divided into o@-and 7r-parts.When certain relations hold between some integrals of o@-e1ectrons,the a-part of the energy of the

3See, for example, E. Hilckel, Z. Physik, 72:812, 1981;G. W. Wheland and L. Pauling, J. Am. Che,n. Soc., 57:2086,1985; H. C. Longuet-Higgins and C. A. Coulson, Trans. Far.Soc., 43:87, 1947; C. A. Coulson and H. C. Longuet-Higgins,Proc. Roy. Soc. London, s.A,191:39;s.A, 192:16, 1947.

system has a maximum in the process of reaction,by which the transition state is defined. In thetransition state a hyperconjugation may takeplace between the initial conjugated system andthe quasi-ir-orbital which may appear near the reaction center. According to the theoretical treatment which has been given in detail in the literature (11), the activation energy, i@E, of the reaction is given by

where

L@E (@E)@+ (z@.E)T, (1)

N@ —v)C@(@E)@='@'-@--— 72+v(ah—aR), (2)

@_‘

in which N is the total number of ,r-orbitals in theisolated conjugated molecule, v and C@are thenumber of electrons (0, 1, or 92)and the coefficientof the rth atomic T-orbital in the jth molecularorbital in the conjugated molecule, respectively,the energy of which is s. The value of is is determined by the type of reaction in the sense of organic electronic theory, and is taken as 0, 1, or 92,according to whether the reagent is electrophilic,radical, or nucleophilic, respectively. a@,and aR arethe Coulomb integrals of the quasi-w-orbital andof the orbital of the reaction center in the reagent,respectively. By the reason given in the originalpaper, aa may in the present case be put equal toa, which is the Coulomb integral at a carbon atom

inbenzene.The terms AE4@and v(aa aR) as well as ‘yare

constant and may be disregarded in discussingreactivity if only the same type of reactions areconsidered, as in the present case. The relativeease of reaction, therefore, can be measured by the

amount of the coefficient of ‘y@in Equation (92).This quantityisreferredto as “super-delocalizability― and denoted by S@,that is

sr==@ (v,_;)C@2(3)

where Xjis given by s3= a + X$ in which@ is theexchange integral between two adjacent 7-orbitalsin benzene.

In the right side of Equation (3) one or twoterms (denoted by suffix f) exist in which@ Xii issmall and v@—v 0. Hence, the magnitude ofSr @5determined predominantly by these terms,especially in a large molecule such as condensedaromatic hydrocarbons. We call the molecular orbitals corresponding to such terms the frontier orbilals. Thus, reactivity in these molecules can bediscussed by calculating only the contribution of

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NAGATA et al.--Eleetronic Structure and Carcinogenic Activity ~35

the frontier orbitals. 3 In almost all the cases, the frontier orbitals coincide with the highest occupied orbital in the electrophilic reaction, with the low- est vacant orbital in the nucleophilic reaction, and with both the above orbitals in the radical reac- tion.

APPLICATION TO THE CARCINOGENIC PROBLEM

It has become clear that an intimate correlation exists between the carcinogenic activities and the frontier electron distributions of nonsubstituted aromatic hydrocarbons.

We designated the position corresponding to the phenanthrene double bond and the position corre- sponding to meso of anthracene the "principal car- cin0genophore TM and the "subsidiary carcinogeno- phore," respectively. The following relations have been found, and, according to these relations, non- substituted aromatic hydrocarbons can be classi- fied into three groups, i.e., (A), (B), and (C).

A) These compounds have both the principal and the subsidiary carcinogenophores and at the same time have sufficiently large values of super- delocalizability at the principal carcinogenophore (Sp). They are carcinogenic.

B) These compounds have the principal car- cinogenophore (p.c.) only. They are slightly car- cinogenie or noncarcinogenic, even if the values of St are above the critical value.

C) These compounds have the subsidiary car- cinogenophore (s.c.) only, are devoid of both the principal and the subsidiary carcinogenophore, or have both carcinogenophores but small values of Sp. They are all noncarcinogenic.

The frontier electron densities calculated at every carbon atom (fl -- $C{ ~) in each compound and the positions of principal and subsidiary car- cinogenophores are indicated in Charts 1 and 2. The values for the compounds which belong to Class (C) are omitted.

The calculated values of super-delocalizability at the principal and subsidiary carcinogenophores are shown in Table 1 and compared with the experi- mental carcinogenic activity. The value of Sp is the sum of the values of super-delocalizability of two carbon atoms at the principal carcinogenophore. 6

s However, in the case when the next orbital is in close proximity to the frontier orbital, the corresponding term must be taken into account.

4 This corresponds to the so-called K-region of the Pull- m a l l s .

s The theoretical ground for th~s summation is easily given by the above-mentioned treatment of the frontier electron theory extended to the case of simultaneous 1,~-addition or substitution, to which, we assume, the carcinogenic reaction should belong.

As generally used, the signs + and - indicate the degree of carcinogenicity. The greater the number of + signs, the greater is the activity. The sign + indicates that the compound is very feebly car- cinogenic; i.e., in some cases it has been reported to be carcinogenic, but in other experiments was not carcinogenic. The - sign indicates that the compound has not been reported to induce tumors.

It can be seen in Table 1 that a close relation exists between the value of super-delocalizability at p.o. and carcinogenic activity. It is rather striking from the physical point of view that such a rela- tion, connecting a biological phenomenon with physics, has been obtained by a calculation in which no arbitrary parameter was introduced.

The critical value of Sp, below which a com- pound is not carcinogenic, is found to be about 0.65 (Table 1). This numerical value has a definite meaning, because Sp is a dimensionless quantity.

The compounds of Class (A) have both the p.o. and s.c.; the values of Sp are larger than the threshold value, and almost all these compounds are carcinogenic. The order of the values of S~ roughly parallels the degree of activity of these compounds. However, in this connection, it should be noted that an attempt to explain very small differences in activity by means of Sp alone may be rather meaningless, since the carcinogenicity varies with the experimental procedure, with the species of test animal, and with differences in the diffusion of the carcinogen into the cell.

Hitherto it has been considered that 1,9.,benzan- thracene is noncarcinogenic (1, 4, 15, 19, 21, 98), but, according to some recent experiments by Steiner et al. (29, 30), it has become clear that this compound is carcinogenic. As is seen from the cal- culations in Table 1, this compound would be ex- pected to carcinogenic. The existing theories based on the supposition that this compound was non- carcinogenic, therefore, must be subjected to a modification, as has been pointed out by Steiner and Falk (30).

As exceptional cases we must refer to 2,3,7,8- dibenzphenanthrene and 2'3'-naphtho-3,4-py- rene. In spite of the reported inactivity of these compounds, the calculated values of Sp are larger than the threshold value. Perhaps they should be retested by experiments of longer duration as in the case of 1,~-benzanthracene.

In general, the value of S, is not so important as that of S~, though the existence of s.c. relates to the activity essentially, as will be stated below. Pullman's opinion (23, ~ ) that the larger the electron density of the meso position (correspond- ing to s.c.) the lower the carcinogenicity has not been cont%med by our resUlts. Thus, the values oi ~

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Cancer Research9236

S. were rather large for 3,4-benzpyrene, which isone of the most potent carcinogens, as well as for3,4,8,9-dibenzpyrene, which is a relatively potentcarcinogen.

The compounds of Class (B) have only p.c. andnot s.c., and the carcinogenicity of these compounds is relatively weak, even though the valueof 5,, is comparatively large. From this fact, it maybe possible to conclude that the existence of s.c. isa necessary, though not a sufficient, condition forcarcinogenicity. This is interesting in relation tothe opinions of Boyland (3) and Kooyman andHeringua (18) who have pointed out the importance of the anthracene meso position.6

Although 3,4-benzphenanthrene and 1,92,3,4-dibenzphenanthrene are definitely carcinogenic, the

‘However, Pullman (28, 24) has reported, against them,that the existence of K-region alone is sufficient for thecarcinogenicity.

values of 5,, for these compounds are below thethreshold value. However, we feel this might bedue to some other factors, for instance, the specialsteric circumstances in these compounds.

The compounds of Class (C) are devoid of thep.c. or otherwise have a p.c. whose 5, is below thethreshold value. Experimentally, these compoundshave been found to be noncarcinogenic. Thereforethe agreement of the calculated results with experiments is very satisfactory.

Thus, the present authors conclude that the existence of a p.c. whose 5, is larger than the threshold value should be necessary for carcinogenic activity; further, the value of 5,, is the most important factor determining the degree of activity.From this point of view it can be said that themain center of reaction is p.c. With the existenceof s.c. alone, there appears to be no activity, evenif the value of 5, is large. But, as is seen from

CHART 1.—Frontier electron distributions and the positions the frontier electron density at each position in the moleculeof principaland subsidiarycarcinogenophoresin the corn- f,; the principalcarcinogenophoreis shownby a thick line;pounds of Class (A). (Numerical values in the Chart indicate the subsidiary carcinogenophore is shown by a black spot.)

.0?4

.038J@.04 ,@,j@066J.203

.0?4

I:2:5:6-DIBENZM@THR4CENE

.068

.162M @uff04@01O

./12('@,'@'cJ@―

.o3,L@ø&@,L@.'.,53.f@6 .186 .15?

1:2:3 :4-D/BENZpyRfN@

.173 .23!.0@5'@1°.O06

@ ‘@66.ac103 00/ .2041I@@@::;0

Q@V7.IV3:4ZP@'@E@f

.135 .070:01 s 02 .023

t66 .120 0/2 .042‘4. ü7,054

2/ .107@52.205

2:3:7:8-D1@NZPHEfVANTHffNE

.082.ooo1c@@.oja

20? .3?6 .177

1:2 -BENZAWTHRACENE

/56 .324 III

@25!J12@@J,@017@0@2J0@.°8a(o7@f @7@qq@.0/7@@ 02/

@fii'@1@.Is6

3:4:8: ?—D/BENZPYRENE

ii? .168

0/

AJ 1fl1h5 I@ L062

2':3'-NAPfrITHO-3:4-PYRENE

.080 .080.@ @02J.04jg@5q@V@.043

1:2:7:8-D1A9@N@'mm@ffNE

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NAGATA et al.—Electronic Structure and Carcinogenic Activity 9237

Table 1, the activity is remarkably decreasedwhen the carcinogen lacks the s.c. even though thevalue of 5, is sufficiently large. Therefore, it seemscertain that, in a sense, the s.c. is connected withthe process of carcinogenesis. Consequently, it isassumed that the s.c., though it is not the maincenter of reaction, plays a sort of subsidiary role inmaking more easy the chemicalcombinationbetween the p.c. and protein. It is concluded, therefore, that the existence of s.c. is also necessary forthe occurrence of activity.

The frontier electron method also appears applicable for explaining the structures of metabolites of carcinogens. The results will be reported inthe near future.

.055.055

080i@@ 4-@i@@

.A14? .0048 5

.255 @‘ .255.21/ .211

SUMMARY

1. The frontier electron method, one of thequantum mechanical methods for explainingchemical reactivity, which has been proposed bysome of the presentauthors,was appliedto theproblem of the carcinogenicactivityof nonsubstituted aromatic hydrocarbons. Frontier electrondistributionsand thesuper-delocalizabilities,whichare the quantitiesdeterminingthe chemicalreactivity of these compounds, were calculated, andthe results were reported.

92.By comparingthecalculatedresultswithexperimental data, the present authors concludedthat two different positions were necessary for the

1:2-BENZPYRENE 1:2:5:6 -DIBENZPHENANTHRENE

.123.17/('@1I7

.IZ/ 1110 4200

.I23(4@(/,@ C(58

.200.05.22/

PI-/ENANTHRENE

.175 .175

.272

0 0 iO

.272 0754.05.172.175.175

PYRENE

.241.129 .129.24/@ ,r@ ,r'?@ 117

0/5.0? .016.01.003 .04 042.04 1)12 @q.005

.018.047 .167.167 .047.098

PICENE

.042042.%47@.124

.2@ .10 /02 2260

.0, 3/ .03 005.13? £138 .088 .139

.0?2.017 .0/7.092

3:4:5:6-D/BfftjJf'/-/EftJANTHR,94E

.099 .09?.01'@2l2?.129(@j@.068

./4&@@A@}•@L@/4J.053 /64 .053.181@ 071

J68 .168

3:4-,5ENZP/-/ENANTHRENE

.000 .091

./30(―@ ./?2@-f@'@.077

@ ).2o2.07/@ 263 00/.014 , 65 .290

@ 002 .06/

.014

/:2:34@-D/BENZm5@f4N77-/R@NE

CHART 2.—Frontier electron distributions and the positions of principal and subsidiary carcinogenophores in the cornpounds of Class (B). (Cf. notes in Chart 1.)

.290 /20 297 1'74083 040 .110('@çô?@.028

/36 /45 035 056 .1/6.12 02' /22 057 008 109,,120203@02 /40 .007 035@ .//6

.30? .038 .174 .2??

CI-IRYSENE

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9288 Cancer Research

carcinogenic activity. They were designated the“principal―and the “subsidiary―carcinogenophores, respectively. An intimate correlation existed between the frontier electron densities or thesuper-delocalizabilities at the two kinds of carcinogenophores and the magnitudes of carcinogenicactivity of these compounds. The value of super

Class Compound.8,4-Benzpyrene1,2,5,6-Dibenzanthracenel,2,8,4-Dibenzpyrene

A 2,8,7,8-Dibenzanthracenel,2-Benzanthracene8,4,8,9-Dibenzpyrene2',8'-Naphtho-8,4-pyrene1,2,7,8-Dibenzanthracene1,2-Benzpyrene1,2,5,6-DibenzphenanthrenePyreneChrysene

B PicenePhenanthrene3,4,5,6-Dibenzphenanthrene8,4-Benzphenanthrene1,2,8,4-Dibenzphenanthrene

2',1'-Anthra-l,2-anthracene2,8,5,6-DibenzphenanthreneAnthanthrene1,2,7,8-Dibenznaphthacenel,2,8,4,&,6-Tribenzanthracene1,2-Benznaphthacene1,2,9,1O-Dibenznaphthacene

C PentapheneV,2'-Anthra-1,2-anthracenePentaceneAnthracene1,2,8,4-DibenzanthraceneNaphthaceneTriphenylenePerylene1,2,6,7-Dibenzpyrene

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3. The center of reaction in carcinogenesismight be the principal carcinogenophore, and thesubsidiary carcinogenophore might play some subsidiary role in carcinogenesis.

TABLE 1

CoMPARIsoN OFTHE VALUESOF SUPER-DELOCALIZABILITIESAT CARcIN0-GENOPHORES WITH CARcINoGENIc ACTiVITIEs

Super.delocaliz

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0.59700.80890.97250.78990.89890 .97410.86490.42870.52581.28180.98480.71590.4876

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1955;15:233-239. Cancer Res   Chikayoshi Nagata, Kenichi Fukui, Teijiro Yonezawa, et al.   Compounds: I. Condensed Aromatic HydrocarbonsElectronic Structure and Carcinogenic Activity of Aromatic

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