J. Phys. Chem. 1993,97, 2385-2394
2385
Photoelectron and ab Initio Molecular Orbital Investigations of Genotoxic Benz[a]anthracene Metabolites: Electronic Influences on DNA Binding Sharon M. Fetzer,f Chao-Ran Huang,? Ronald G. Harvey,: and Pierre R. LeBreton’9t Department of Chemistry, The University of Illinois at Chicago, Chicago, Illinois 60680, and Ben May Institute, University of Chicago, Chicago, Illinois 60637 Received: August 4, 1992; In Final Form: October 28, 1992
Gas-phase He(1) UV photoelectron (PE) spectra have been measured for nine benz[u]anthracene (BA) and alkyl-BA metabolites. Among the metabolites examined are the diols, (*)-trunr-3,4-dihydroxy-3,4-dihydroBA (BAD); the 7-methyl (MBAD), 7-ethyl (EBAD) and 7,12-dimethyl (DMBAD) derivatives of BAD; and cis-5,6-dihydroxy-5,6-dihydro-BA.Also investigated were the bay-region diol epoxides, (f)-trunr-3,4-dihydroxyunti-l,2-epoxy-1,2,3,4-tetrahydro-BA(BADE); the 7-methyl (MBADE) and 7-ethyl (EBADE) derivatives of BADE; and the K-region epoxide, BA-5,6-oxide (BAO). Of these metabolites, the diols, BAD, MBAD, and DMBAD, are potent proximate carcinogens, which in vivo are enzymatically activated to the ultimate carcinogens, BADE, MBADE, and the corresponding 7,12-dimethyl-BA epoxide. Current evidence indicates that the covalent binding, and possibly the reversible physical binding, of hydrocarbon epoxides to DNA influence the genotoxic activities of these molecules. Photoelectron spectra have been assigned by comparison with results from semiempirical HAM/3 and ab initio SCF molecular orbital calculations employing the 4-31G basis set. A comparison of DNA association constants and IP’s for seven hydrocarbons with the naphthalene or anthracene T systems and for the BA diols examined here demonstrates that, as the IP’s of structurally similar unhindered hydrocarbons and BA diols decrease, the association constants increase. For structurally similar hydrocarbons and BA metabolites, average polarizabilities, calculated at the 4-31G level, also increase as the a ionization potentials decrease. A relationship between polarizability and reversible binding to DNA is suggested by a comparison of polarization energy maps calculated, at the4-3 1G level, for anthracene and 9,lO-dimethylanthracene (9,lO-DMA). In calculations using a 0.5 eu positive probe charge, the map calculated for 9,lO-DMA has contours that over large regions, are 1.0-1.5 kcal/mol more attractive than corresponding contours in the map for anthracene. The present results indicating that the first IP’s of the epoxides decrease in the order BAO (7.58 eV) > BADE (7.37 eV) > MBADE (7.28 eV) = EBADE (7.27 eV) areconsistent with previously reported observations that alkylation of BADE in the 7- and 12-positions enhances reactivity and that bay-region diol epoxides are more reactive than K-region epoxides. The greater reactivity of bay-region diol epoxides versus K-region epoxides is also reflected in the electron distributions of the highest occupied molecular orbitals (HOMO’S). For BADE, but not BAO, the HOMO has large electron density in a region that aids stabilization of transition states occurring in reactions with DNA.
Bay Region
Introduction An understanding of the structural features of polycyclic aromatic hydrocarbons (PAH’s) that contribute to the DNA physical and covalent binding properties of these molecules and how these binding properties relate to carcinogenic activity has long been sought.’-1° Recent research has led to the identification of bay-region diolepoxide metabolites as the principal active carcinogenic species, termed ultimate carcinogen^.^^^+^^ The reactive epoxides bind covalently to DNA, leading to mutations and ultimately to tumor induction. Figure 1 shows the structure of the bay-region diolepoxide, (f)-trans-3,4-dihydroxy-anti-1,2epoxy-1,2,3,4-tetrahydrobenz[a]anthracene (BADE), derived frombenz[a]anthracene (BA). Invivo, the immediate metabolic precursor of BADE is a diol, (f)-truns-3,4-dihydroxy-3,4-dihydroBA (BAD), which is an example of what is termed a proximate carcinogen. Insight into factors that influence the genotoxic potency of PAH epoxides has been provided by the bay-region theory of hydrocarbon carcinogenic a~tivity.~This electronic theory postulates that PAH metabolites that possess a vicinal dihydrodiol epoxide with the epoxide group in a bay region are more reactive and more carcinogenic than PAH’s with epoxide groups in nonbay regions. Figure 1 shows the structure of BADE and of the
’ University of Illinois at Chicago. t
University of Chicago.
W -tnn89,4dlhydroxy-a~~/-1,2.~poxy1,2,3,4-~tmhydro~nz(a)~nthr~~ne (BADE)
/K-Region Bonz(r)~nthr~elw-S,~oxldo
Figure 1. Structures of the benz[a]anthracene bay-region diolepoxide, (f)-rrans-3,4-dihydroxy-anti-l,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene (BADE), and the K-region epoxide, benz[u]anthracene-5,6oxide (BAO).
non-bay-region epoxide, BA-5,6-oxide (BAO). Benz[a]anthracene46-oxide is a example of what is called a K-region epoxide.]’ It is likely that electrophilic attack of DNA by hydrocarbon epoxides is SN1-like and proceeds through protonstabilized transition states in which the hydrocarbon exhibits significant carbonium ion The bay-region theory directly relates the ease of carbonium ion formation to the reactivity toward DNA and to Carcinogenic activity. In application of the theory, the delocalizationenergy of the carbonium ion r system, calculated within the framework of Hijckel theory, has been employed as a measure of chemical reactivity and carcinogenic activity.
0022-3654/93/2091-2385So4.~0~0 0 1993 American Chemical Society
2386 The Journal of Physical Chemistry, Vol. 97, No. 10, 199'3
Fetzer et al.
Methods
Consistent with the bay-region theory, the hydrolysis rate constant for the bay-region diolepoxide derived from the carcinogen benzo[a]pyrene (BP), (f)-frans-7,8-dihydroxy-a~?~-9,10-epoxy-7,8,9,1O-tetrahydro-BP(BPDE), ismorethan 180times larger than the rate constants for hydrolysis and rearrangement of the corresponding K-region epoxide, BP-4,5-oxide (BPO).I Both hydrolysis and rearrangement reactions proceed through carboniumion intermediates. The higher reactivity of bay-region diolepoxides versus K-region epoxides is paralleled by their mutagenic and carcinogenic a~tivities.~,~fJ3-'~ For example, BADE is 40 to 50 times more tumorigenic in Chinese hamsters than BA0.4f The reactivity of epoxide-containing metabolites of PAH's toward DNA is an important factor contributing to the overall mutagenic and carcinogenic potency of these molecules. For example, as the rates for neutral hydrolysis reactions of similar isomers of polycyclic aromatic diolepoxides increase, the mutagenic potency of the diolepoxides in cultured S. typhimurium TA 100 and Chinese hamsters V79 cells generally increases!* However, other properties in addition to reactivity are also important. For instance, BPO and BAO are better substrates for detoxifying enzymes, such as epoxide hydrolases, than BPDE or BADE.18J9 Physical binding of hydrocarbonmetabolitesto DNA is another propertythat may influence mutagenicand carcinogenic activity. Measurements of overall, pseudo-first-order rate constants for reactions of BAO, BPDE, and BPO indicate that the reversible binding of these epoxides to DNA greatly enhances their reactivities.~.~a~d~c,9~~~28 In experiments carried out at 23 OC, at a pH of 7.1 in 1.OmM sodium cacodylate, overall, pseudofirst-order rate constants for hydrolysis and rearrangement reactions of these epoxides are 4.9 X 10' to 3.1 X lo3times faster in native calf thymus DNA (0.20 mM in PO4-) than in buffer alone.' The observed catalysis of epoxide hydrolysis and rearrangement by DNA has led to the suggestion that DNA also autocatalyzes reactions leading to the formation of DNA adducts.20 Differences in the genotoxic activity of mutagenic and carcinogenic hydrocarbons depend not only on the aromatic structure of epoxide-containingmetabolitesbut also on the nature of substituent groups. For example, BA and 7-ethyl-BA are essentially inactive as complete carcinogen^,^^ while 7,12dimethyl-BA is one of the most potent carcinogenichydrocarbons known, and the 6-, 7-, 8-, and 12-methyl-BA'sexhibit intermediate levels of carcinogenic activity.298 In a previous paper,3O we reported and assigned the photoelectron spectra of trans-7,8-dihydroxy-7,8-dihydro-BPand BPDE, the proximate and ultimate carcinogens derived from bcnzo[a]pyrene. The first goal of the present investigation is to measure the photoelectron spectra of benz[a]anthracene and of alkylbenz[a]anthracene metabolites. We have examinedfive BA diols and four epoxides. The diols are cis-5,6-dihydroxy-5,6dihydro-BA (BA56D)and (f)-tranr-3,4-dihydroxy-3,4-dihydroBA (BAD) and the 7-methyl (MBAD), 7-ethyl (EBAD), and 7,12-dimethyI (DMBAD) derivativesof BAD. The epoxidesare BAO and BADE, and the 7-methyl (MBADE) and 7-ethyl (EBADE) derivatives of BADE. The second goal is to employ descriptions of BA and alkyl-BA metabolites, provided by the photoelectron data and by results from ab initio SCF molecular orbital calculations, to obtain a clearer picture of the manner in which valence electronic structure influences the physical and covalent binding of these molecules to DNA.
Gas-phase photoelectron spectra were measured with a PerkinElmer PS-18 photoelectronspectrometer equipped with a heated probe and a He(1) lamp. Vertical IP's were obtained fromspectra calibrated with the 2P3/zand bands of Ar and Xe. The reported IPSare accurate to within f0.05eV. Samples of BAO and BA56D were obtained from the Midwest Research Institute through the NCI Chemical Carcinogen Repository. Samples of BAD,3' MBAD,32EBAD,33J4DMBAD,j5BADE,36MBADE,j4 and EBADE33*34 were synthesized by using previously described procedures. In order to determine whether decomposition occurred, samples were analyzed by HPLC before and after PE spectra were measured. A Beckman Model 420 chromatograph with a Du Pont Zorbox SIL silica column was used. Samples were eluted with a THF/hexane (30/70) solvent mixture. For the epoxides, the HPLC results indicated that less than 3% decomposition occurred during the PE measurements. For the diols, there was no detectable decomposition. MolecularOrbital Cplculatiolrs. Theoretical IP's were obtained by applying Koopmans' theorem37 to the results from semiempirical HAM/338 and from ab initio SCF molecular orbital calculations, employing a 4-3 1G39basis set. The calculations were performed on Cray X-MP/48 and IBM 3090/200 E/VF and 600 E/VFcomputers. The Gaussian 90 program was used.4o Polarizabilities were obtained from the 4-3 1G wave functions as numerical derivatives of the dipole moments obtained by using coupled, perturbed HartreeFock theory.4' For the calculationsof ionization potentialsand polarizabilities, the geometries of toluene,43 naphthalene,4 2-methylnaphthalene (2-MN),45anthracene,469-methylanthracene (99,lO-dimethylanthracene (9,10-DMA),47pyrene,48 BPDE,49and BPOSOwere taken from crystal data. The geometry of 1-methylnaphthalene (1-MN) was based on the crystal structure of 8-meth~l-BA.~'The geometries of BAD, MBAD, and EBAD were obtained by combining crystallographic data for 9-MA with a geometry for (f)-trans-l,2-dihydroxy-1,2dihydronaphthalene optimized at the 3-21G Geometries for BADE, MBADE, and EBADE were obtained by combining the geometries for the corresponding diols with crystallographic data for the epoxide group in BPDE.49 The geometry of BAO was obtained by combiningthe crystal structure of phenanthrene9,10-oxide53 with the structure of ben~ene.~2 The geometry of BA56D was based on the crystal structure of BAO; however, the saturated ring and the hydroxyl group geometrieswere optimized by using theAM1 method.55Thegeometryof 1,2,3,4-tetrahydroBA (1,2,3,4-HBA) was obtained by combiningcrystal structures of anthracene and cycl~hexane.~~ The results from 4-31GSCFcalculations were used toconstruct MO diagrams in which the size of each atomic orbital is proportional to the corresponding molecular orbital coefficient. For p orbitals, the coefficientsof the inner Gaussian terms of the 4-31G expansion were used; for s orbitals, the coefficients of the outer terms were used.56 Only atomic orbitals with coefficients greater than 0.15 are shown in the diagrams. Polarization Energy Maps. Ab initio 4-31G polarization energies were calculated for the interaction of the metabolite modelcompounds, anthraceneand 9,10-DMA,witha 0.5-eupoint charge located at varying positions on a grid 1.6 A above the planes containing the aromatic rings of the two molecules. The distance between the point charge and the hydrocarbon is equal to half the distance between the stacked bases of DNA in the B conformati~n.~~ For each molecule, polarization energies were calculatedat 289gridpoints,whichwerespactdat0.15-Aintervals in the plane above the hydrocarbon. For the calculation of polarization energy maps, DZh and C2, geometries of anthracene and 9,lO-DMA were used in order to reduce computation time. For the carbon atoms in the ring systems standard aromatic bond lengths and angles were empl0yed.5~For the methyl groups of
Genotoxic Benz [a]anthracene Metabolites
The Journal of Physical Chemistry, Vol. 97, No. 10, 1993 2387
..J ,
8.0
10.0
12.0
14.0
8.0
1
10.0
1
1z.o
1
14.0
IONIZATION POTENTIAL (eV)
Figure 2. He(1) UV photoelectron spectra of the benz[u]anthracene diols, (*)-rrom-3,4-dihydroxy-3,4-dihydro-BA(BAD), of its 7-methy1, 7-ethyl, and 7,12-dimethyl derivatives (MBAD, EBAD, and DMBAD), (BA56D) are shown on the and of cis-5,6-dihydroxy-5,6-dihydro-BA left. Spectra of the bay-region diolepoxide (*)-truns-3,4-dihydroxyrmti-l,2-epoxy-l,2,3,4-tetrahydro-BA (BADE),of its 7-methyland 7-ethyl derivatives (MBAD and EBAD), and of the K-region epoxide, BA-5,6oxide (BAO), are shown on the right.
9,10-DMA, the C-C and C-H bond lengths were 1.54 and 1.08 bond angles were 109.5'. At each point on the grid, the polarization energy was taken to be the difference between the interaction energy of the molecule with the point chargecalculated by using two different molecularwave functions. In the first calculation, the wave function for the isolated molecule was employed. In the second, the optimized wave function for the molecule in the presence of the point charge was employed. Contour maps were constructed from polarization energies calculated at all grid points.
A and the C-C-H
Result5 PhotdmtronSpectrp. Figure 2 shows He(1) UV photoelectron spectra and assignmentsfor bands arising from the upper occupied T and oxygen atom lone-pair orbitals for the BA and alkyl-BA diols and epoxides examined. The spectra of the bay-region diolepoxide precursors, BAD, MBAD, EBAD, and DMBAD, shown in the upper portion of the panel on the left, are similar in appearance. Each spectrumexhibits five clearly resolved bands with vertical IP's between 7.0 and 10.0 eV. Each of these bands arises from a 7r orbital. For DMBAD, the sixth highest occupied T orbital ( T ~ gives ) rise to a resolved band at 10.06 eV. The lowest energy I P S of BAD, MBAD, EBAD, and DMBAD decrease in the order 7.42,7.26,7.24, and 7.19 eV, respectively. Similarly, for MBAD, EBAD, and DMBAD, the second through fifth highest occupied 7r orbitals ( 7 r 2 to as) have vertical IP's that are smaller than those of correspondingorbitals in BAD. Bands arising from the 7r6 orbitals of BAD, MBAD, and EBAD occur in unresolved parts of the spectra above 10.1 eV. The PE spectrum of the K-region diol, BA56D, shown at the bottom of the left-hand panel, contains clearly resolved, low-
energy bands, at 7.97 and 8.48 eV. These arise from the TIand 7 r 2 orbitals. The 7r3 and 7r4 orbitals give rise to overlappingbands at 9.23 and 9.59 eV. The band associated with the 7r5 orbital is resolved and occurs at 10.08 eV. At higher energiesthe spectrum is unresolved. In the spectra of all of the diols shown at the left in Figure 2, the bands associatedwith the highest occupiedoxygen atom lone-pair orbitals are assigned to the region above 10.1 eV. This is consistent with the observation that, in cyclopentanol,the smallest oxygen atom lone-pair ionization potential is 10.21eV.58 The panel on the right of Figure 2 shows spectra and assignments for the BA and alkyl-BA epoxides. The spectra of the bay-region diolepoxides,BADE, MBADE, and EBADE, each exhibit two resolved, low-energy 7r bands with IP's between 7.2 and 7.9 eV. These are followed by two poorly resolved bands arising from the 7r3 and 7r4 orbitals with IP's between 8.5 and 9.2 eV. For BADE, MBADE, and EBADE, the 7r5 orbitals have well-resolved bands with energies between 9.5 and 9.9 eV. Like the diols, the oxygen atom lone-pairorbitals of the hydroxygroups in the epoxides, BADE, MBADE, and EBADE, have IPSabove 10.0eV and give rise to bands that occur in poorly resolved regions of the spectra. The PE spectrum of the K-region epoxide, BAO, shown at the bottom of the right-hand panel, exhibits only two clearly resolved bands. These have been assigned to the 7r1 and 7r2 orbitals, and have IP's of 7.58 and 8.16 eV, respectively. The band arising from the 7r3 orbital appears as a shoulder at 9.08 eV. The rest of the spectrum is unresolved. The epoxidegroup lone-pair bands of BAO, as well as those of BADE, MBADE, and EBADE, have been assigned to the energy region above 10.1 eV. This is consistent with the observation that the first lone-pair IP in ethylene oxide is 10.57 eV.59 Molecular Orbital Calculations. Ben~~Jantbracene Diols. Figure 3 compares experimental IP's for the BA diols with IP's obtained from HAM/3 calculations. The HAM/3 calculations yield ionization potentials for the T I orbitals of the BA diols that agree with experiment to within 0.3 eV. For the more tightly bound 7r2 to 7r5 orbitals, the difference between the experimental IP's and the IP's obtained from HAM/3 calculations is less than 0.56 eV. In somecases,the HAM/3 calculationsfail to correctlyindicate that in MBAD, EBAD, and DMBAD the ionization potentials for the 7rl to 7r5 orbitals are smaller than the IP's of corresponding orbitals in BAD. According to the HAM/3 calculations, the r l ionization potentials in BAD and EBAD are equal, and the 7r4 ionization potential in EBAD is 0.10 eV larger than in BAD. Experimentally, the ionization potentials of the T I and 7r4 orbitals of EBAD are 0.18 and 0.14 eV smaller than the corresponding IP's of BAD. The HAM/3 calculations accurately predict that I P S of the 7rl and 7r2 orbitals of the K-region diol, BA56D, are larger than those of correspondingorbitals in the bay-regiondiol, BAD. According to the HAM/3 results, the I P Sfor the al and u2orbitals in BA56D are 0.80 and 0.19 eV larger. Experimentally, they are 0.55 eV larger. The HAM/3 calculations less accurately describe the ordering of the 7r4 ionization potentials in BA56D and BAD. According to the HAM/3 results, the ionization potential of the 7r4 orbital in BA56D is 0.10 eV smaller than that in BAD. Experimentally, it is 0.37 eV larger. Figure 4 contains ionization potentials and orbital diagrams obtained fromresultsof ab initioSCFcalculations with the4-31G basis set. The absolute values of the first IP's obtained from the 4-3 1Gcalculationsare0.461.06 eV smallerthan theexperimental values and, in this regard, are less accurate than results obtained from the HAM/3 calculations. Nevertheless, patterns of IP's obtained from the ab initio and semiemperical calculations are similar, and, in some ways, the results from the 4-31Gcalculations are more reliable than results from the HAM/3 calculations. For example, in contrast to results from the HAM/3 calculations, the 4-31G results accurately indicate that the IP's of all five of
Fetzer et al.
2388 The Journal of Physical Chemistty, Vol. 97, No. 10, 1993 EXPERIMEKTAL BAD
z
MEAD
a.ol t“
€BAD
DMBAD
BAS60
‘
9.0
lo*o 11.0
I
5
-..--“5
“5
/--
*
____... ---n 5 “g
n*”
I
-1 HAMD
I
“
BAD
MBAD
€BAD
DMBAD
BAS60
I
I
10.0
1 I
“6
Figure 3. Experimental ionization potentials for the BA diols, BAD, MBAD, EBAD, DMBAD, and BA56D, shown in the top panel, are compared with theoretical ionization potentials obtained from semiempirical HAM/3 calculations, shown in the bottom panel. In the top panel shaded areas denote energy regions of the PE spectra that contain overlapping bands for which precise ionization potentials have not been obtained.
the highest Occupied a orbitals in BAD are larger than those of corresponding orbitals in MBAD, EBAD, and DMBAD. However, like the HAM/3 calculations, the 4-3 1G calculations fail to accurately predict differences between corresponding IP’s in BA56D and BAD for some of the more tightly bound a orbitals. For example, the 4-31G calculations predict that the IP of the a4 orbital in BA56D is 0.78 eV smaller than that of the a4orbital in BAD. Experimentally, the IP of the a4orbital in BA56D is 0.37 eV larger. For the bay-region diols, BAD, MBAD, EBAD, and DMBAD, the results from the 4-31G calculations differ from those of the HAM/3 calculations in predicting that the IP’s of the a6 orbitals are smaller than those of the nl orbitals. In the spectra of BAD, MBAD, and EBAD the energy region above 10.0 eV is poorly resolved and the energetic ordering of the nl and the a 6 orbitals cannot be determinedat this time. For DMBAD, the assignment of the band at 10.06 eV to the a6 orbital and the assignment of
the band associated with the nl orbital to an energy above 10.1 eV are consistent with the observation that methyl substitution reduces the IP‘s of both a and lone-pair orbitals in aromatic molecules containing heteroatoms such as nitrogen or oxygen. However, when the methyl substitution does not occur at a heteroatom, the largest reduction in IP generally occurs in one of the a orbitals.6°.6’ w a w t b r a c e n e Epoxides. Figure 5 comparesexperimental IP’s of BA epoxides with theoretical IP’s from HAM/3 calculations. The calculated IPS for the alorbitals of the epoxides, BADE, MBADE, EBADE, and BAO, are 0.234.77 eV smaller than the experimental IP’s. For the a2 and as orbitals in BADE, MBADE, and EBADE, and for the a2 and the a3 orbitals in BAO, all of which give rise to resolved PE bands, the IP’sobtained from HAM/3 calculations differ from the experimental values by 0.03-1.33 eV. The results of the HAM/3 calculations for the bay-region diolepoxides, like those for the diols, fail, in some cases, to accurately indicate that alkylation reduces the IP’s of the upper occupied T orbitals compared to BADE. The HAM/3 calculations predict that, in EBADE, the IP of the a2 orbital is 0.50 eV larger than that in BADE. Experimentally, the IP of the ‘112 orbital in EBADE is 0.06 eV smaller. While the HAM/3 calculationsaccurately predict that the IP of the a1 orbital in the K-region epoxide BAO is larger than in the bay-region diolepoxide, BADE, the computed differencein IP’s (0.75 eV) is larger than theexperimentaldifference (0.21 eV). The HAM/3 calculations more accurately predict the differencebetween the IP’s of the 1 2 orbitals in BAO and BADE. According to the HAM/3 results, the 1 2 ionization potential in BAO is 0.36 eV larger than that in BADE. Experimentally, it is 0.30 eV larger. Figure 6 gives IP’s and orbital diagrams obtained from 4-3 1G calculations on the BA epoxides. For the epoxides, unlike the diols, theoretical ionization potentials obtained from the 4-3 1G calculations aresimilarin accuracy to IP’sobtained from HAM/3 calculations. The a ionization potentialsobtained from the 4-3 1G calculationson the epoxides are 0.16482 eV smaller than the experimental IP’s. For the epoxides, as for the diols, the 4-31G calculations, unlike the HAM/3 calculations, predict that all five of the highest occupied T orbitals in MBADE and EBADE have smaller IP’s than corresponding orbitals in BADE. The 4-31G calculations predict that the IP‘s of the a1 to as orbitals in the alkylated epoxides are 0.02-0.23 eV smaller than those in BADE. In agreement with the HAM/3 results and experiment, the 4-31G calculations indicate that the IP of the aIorbital in the K-region epoxide, BAO, is larger than that in the bay-region diolepoxide, BADE. However, the calculated difference (0.87 eV), like that obtained from the HAM/3 results, is significantly larger than the experimental difference. For the a2 orbitals, the energetic ordering of IP‘s in BAO and BADE is less accurately predicted by the 4-31G calculations than by the HAM/3 calculations. The 4-31G calculationspredict that the IP of the a2 orbital in BAO is 0.11 eV smaller than that in BADE. For the bay-region diolepoxides, like the bay-region diols, the 4-3 1G calculations predict a different energetic interspacingof a and lone-pair orbitals than that predicted by the HAM/3 calculations. Incontrast to the HAM/3 results, the4-31G results indicate that, for BADE, MBADE, and EBADE, the IPSof the as orbitals are smaller than those of the nl orbitals. As pointed out above, a comparison with the experimental IP of the highest oocupied lone-pair orbitalin ethyleneoxides9supports theordering predicted by the 4-31G calculations. Discussion Electronic Influences on tbe Reversible Binding of anthraceneMetabolites to DNA. While the covalent modification of DNA by epoxide-containingmetabolites of aromatic hydrocarbonsis criticalto the carcinogenicpotency of these mole~ules,~J
Genotoxic Benz[a]anthracene Metabolites
The Journal of Physical Chemistry, Vol. 97, No. 10, 1993 2309
Figure 4. Theoretical ionization potentials and orbital diagrams for BAD, MBAD, EBAD, DMBAD, and BA56D obtained from ab initio SCF calculations employing the 4-3 1G basis set.
reactions of hydrocarbon epoxides are strongly influenced by the ionization potentials of all of the moleculesconsidered. The results reversible binding of these epoxides to DNA.l~5-7*8a~9*20~22-27~6245 in the table demonstrate that, in cases where comparison is Specifically, the formation of DNA complexes catalyzes hydropossible, the polarizabilitiesobtained from the ahc method agree carbon epoxide reactions. This catalysis is similar to that of the remarkably well with experimental polarizabilities. The maxbenzidine rearrangement of 1,2-diphenylhydrazine and of the imum difference is less than 14%. The polarizabilitiesobtained hydrolysis of p-nitrobenzaldehyde diethyl acetal by polyanionic from the 4-31G calculations are 17-3296 smaller than the micelles, such as those formed from sodium lauryl s~lfate.6~.6~ experimental polarizabilities. However, for the hydrocarbons All of these reactions are acid catalyzed. In micelles and in DNA, examined, the ordering of the polarizabilities obtained from the the observed enhanced reactivity is due to high hydronium ion 4-3 1G calculationsgenerally agree with experiment and with the concentrations that occur at the water interface with anionic values obtained from. the ahc method. For the BA metabolites polymeric structures.23@@ investigated, the ordering of polarizabilities, obtained from the Because of the small association constants (103-105 M-1) for 4-3 1G calculations, is also similar to that obtained from the ahc the reversible binding of neutral aromatic ligands to DNA in method. aqueous s o l u t i ~ n , ~ ~ ~there J ~ , ~have * ~ *been only a few measureOne difference between results obtained from the 4-31G ments of thermodynamicconstants for the reversible binding of calculations and from the ahc method is that, for metabolites hydrocarbon metabolites to DNA.'*70*71173 However, results from with small structural differences, the 4-3 1G calculationspredict these measurements indicate that, in the range 23-25 OC, the different polarizabilities while, in some cases, the ahc method enthalpic contribution to the free energy of binding of benzopredicts equal polarizabilities. This is because the results from [alpyrene metabolites to DNA is two to five times larger than the ahc method rely solely on the number of each type of atom the entropic contribution. I +70+7 I in the molecule and on the bonding hybridization. For example, Current evidence indicates that the specificity observed in the the ahc method predicts that the polarizabilities of BAD and stacking of nucleotide bases is significantly influenced by dipoleBA56D are equal and that the polarizabilities of EBAD and induced dipole and dispersion forces, which increase as the DMBAD are equal. The polarizabilitiesobtained from the ab polarizabilitiesof the interacting partnersincrease.74For example, initio calculations account for differences in the T electronic dipole and London dispersionforces are believed to largely account structuresof BAD versus BA56D and of EBAD versus DMBAD. for the observation that purines form stronger stacked complexes In this regard, polarizabilities obtained from the ab initio than pyrimidines, and that complexes formed from methylated calculations are more realistic. bases are stronger than complexes formed from nonmethylated While the polarizabilities of a group of structurally related bases.74 It is likely that van der Waals forces also influence the atomsor molecules increase as the IP's decrease,85a consideration association constants for the reversible intercalation of hydroof all of the molecules listed in Table I indicates that there is no carbon metabolites into double-stranded DNA.1$73 simple relationship between the IP's and the polarizabilities Table I compares average molecular polarizabilitiesobtained obtained from the ab initio calculations. However, if comparisons from ab initio SCF 4-31G calculations on a series of aromatic are made only between molecules that are structurally similar, hydrocarbons and BA metabolites with polarizabilitiesobtained namely, the hydrocarbons, the diols, and the epoxides,the expected by using a semiempirical method based on atomic hybrid relationship is generally observed. This is demonstrated in Figure components ah^).^^ Table I also contains experimental polar7. The upper panel of Figure 7 shows a plot of hydrocarbon izabilities where available. Finally, the table lists the first T polarizabilities obtained from the 4-3 1G calculations versus
2390 The Journal of Physical Chemistry, Vol. 97. No. 10, 1993 EXPERIMENTAL
-
"1 -____._.. J
9 c
"2 '8.0 .OI
1
9.0
--
______
"2 *-
=2
"1
"2
"3 -
"5
,.-__--
10.0
"1
_.-.-- -
t i.. =5
-
"1
...=
-
11.0
HAW3 BADE
MBADE
EBADE
BAO
8.0 n
t
Y
z A
g
9.0
2 2
Q
2
!Y
z
E!
10.0
" "1
Figure 5. Experimental ionization potentials for the BA epoxides BADE, MBADE, EBADE, and BAO, shown in the top panel, are compared with theoretical ionization potentials obtained from HAM/3 calculations, shown in the bottom panel. In the top panel shaded areas denote energy regions of the spectra that contain overlapping bands.
experimental IPS. The lower panel shows similar results for the BA diols and epoxides. The results in the lower panel indicate that, even though both the diols and the epoxides contain only C, 0,and H atoms, a different relationshipbetween the IP's and the polarizabilities exists for these two classes of molecules. If dipole-induceddipole and dispersion forces strongly influence reversible binding interactions between aromatic hydrocarbons and DNA, it is reasonable to expect that the general inverse correlation between polarizabilities and I P S is also reflected in the association constants for the binding of structurally related hydrocarbonsto DNA. According to this line of reasoning, the association constants are expected to increase as the IP's decrease. However, the inverse relationship between I P S and binding constants for the intercalation of aromatic hydrocarbons into DNA is strongly modulated by the DNA base sequence25and by the polaritylJ~8b-c~10~72 and steric properties of the hydroca~bon.8b,d-e.8~~~ These factors influence the ease with which hydrocarbons and BA metabolite ligands insert between the bases of DNA and the contact area between the ligands and the bases after the insertion has occurred. Nevertheless, in cases where
Fetzer et al. polarities and steric properties are similar, binding data support the existence of an inverse relationship between IP's and DNA association constants for aromatic molecules. This is demonstratedby the results in the upper panel of Figure 8, which indicatesthat for the seven naphthalene and anthracene aromatic systems considered the association constants increase as the ?r ionization potentialsdecrease. While only limited data are available, it appears that similar behavior is exhibited by the benz[a]anthracenediols, BA56D, BAD, and MBAD. In earlier m e a s u r e m e n t ~ , ~diols J ~ , ~analogous ~ to BAD and BA56D have been used as model compoundsto comparethe relative magnitudes of DNA association constants for bay-region diolepoxides and the K-region epoxides of BP and BA. A plot of DNA association constants for BA56D, BAD, and MBAD is shown in the bottom panel of Figure 8. Again the association constants increase as the I P Sdecrease. However, the strong sensitivity of association constants to steric effects is also indicated by the results in the bottom panel. For the moresterically hindered ethyl and dimethyl diols, EBAD and DMBAD, the smaller IP's and larger polarizabilities,compared to BAD and MBAD, are not accompanied by larger but by smaller association constants. For DMBAD, the nonplanar, partially saturated angular ring and the methyl groups at the 7- and 12-positions permit unhindered insertion into DNA only at the ring containing the C8 to C11 atoms. For EBAD, it is likely that binding is inhibited by the ethyl group, which has a van der Waals diameter (5.8 A) that is larger than the distance (3.3 A) between stacked bases in B-DNA.90 The steric inhibition of DNA binding exhibited by DMBAD and EBAD is similar to that observed for metabolites of benzo[a]pyrene with bulky substituents at the l - p o ~ i t i o n . ~ ~ . ~ ~ It is interesting to note that while the dimethyl-substituted diol, DMBAD, has a smaller association constant than the unmethylated diol, BAD, methyl substitution in some cases enhances binding. For example, the methylated derivatives, 9,10-DMA and MBAD, have association constants that are 6.7 and 1.6 times larger than those of anthracene and BAD, respectively. While these differences in binding are reflected by differences in IP's and in polarizabilities,they can also be examined in a more localized way. Localized differences in polarizabilities are illustrated by the 4-31G polarization energy maps shown for anthraceneat the top and for 9,lO-DMA at the bottom of Figure 9. Because of the large point charge used to calculate the maps, the energy associated with a specific point on either map is larger than the polarization energy for aromatichydrocarboncomplexes with nucleotide bases. However, differences between the maps illustratedifferences in local polarization energy contributionsto interactionsinvolving anthracene and 9,lO-DMA. A comparison of the maps indicatesthat methyl substitutionin 9,lO-DMA gives rise to more attractive contours above the aromatic rings. This is illustrated by the -28 kcal/mol contours in the vicinity of the C9 and C 10 atoms. The larger7r polarization energies and smaller ?r ionization potentialsIOof 9,10-DMA, compared to anthracene, provide support for earlier claims, based on investigations of stacked complexes formed from substitutedindoles, that the most importantindividual contributions to the polarization energy arise from the highest occupied ?r orbitals.92 The observation that differences in polarization energies between 9,lO-DMA and anthracene occur over regions that, in DNA complexes, are expected to be in close contact with nucleotide bases is consistent with the observed differences in the DNA association constants for 9,lO-DMA and anthracene. Electronic Influences on the Reactivities of Benz[rr]anthracene Epoxides. Both the inherent reactivities of hydrocarbon epoxides, measured, for example,in hydrolysis reactions without DNA,4a*93 and the association constants of these epoxides for reversible binding to DNA' influence the overall pseudo-first-order rate constants for hydrocarbon epoxidereactions in systemscontaining
The Journal of Physical Chemistry, Vol. 97, No. 10, 1993 2391
Genotoxic Benz [a]anthracene Metabolites
I----
---"1
Figure 6. Theoretical ionization potentials and orbital diagrams for BADE, MBADE, EBADE, and BAO obtained from 4-31G SCF calculations.
TABLE I: Polarizabilities and Ionization Potentials of
40
Hydrocarbons and Benz[aJanthracene Diols and Epoxides molecule benzene toluene naphthalene 1-methylnaphthalene 2-methylnaphthalene anthracene 9-meth ylanthracene 9,lO-dimethylanthracene pyrene
polarizabilitya 4-31G ahc exptl
7.07 8.75 13.19 14.62 14.71 20.51 21.96 24.14 22.72 1,2,3,4-tetrahydrobenz[a]- 26.81 anthracene benzo[a] pyrene 30.02 BA56D 24.16 BAD 29.03 MBAD 30.74 EBAD 31.03 DMBAD 32.59 BAO 25.07 BADE 27.08 MBADE 30.74 EBADE 33.10
10.40 12.25 16.59 18.43 18.43 22.77 24.62 26.46 25.49 29.40 33.14 30.45 30.45 32.29 34.14 34.14 29.06 30.62 32.48 34.31
10.3oE 11.83c 17.48/ 19.14f 19.74f 25.93.f 29.08' 29.34
30
ionization potentialb 9.2Sd 8.83d 8.19 7.8Sh 7.93h 7.47g 7.24h 7.14 7.42k 7.17' 7.1 2k 7.97 7.42 7.26 7.24 7.19 7.58 7.37 7.28 7.27
,
~
I
.
~
.
mBP
a m a TOLUENE
ao
7.0
-_-
. -
.
90
IONIZATION POTENTIAL lev) 34 I\- - - -1 -
-> 5
32
30
m
g
28
26
24
71.0
7.2
7.4
7.6
7.8
8.0
IONIZATION POTENTIAL (eV)
In A3. In eV. Taken from ref 75. Taken from ref 76. Taken from ref 77. /Taken from refs 78 and 79. g Taken from ref 80. Taken from ref 81. Taken from ref 82. J Taken from ref 10. Taken from ref 30. Taken from ref 83.
DNA. When corresponding bay- and K-region metabolites of BA and BP are compared, it is found that the bay-region metabolites have larger DNA association c o n ~ t a n t s . ' J For ~~~~ BP diols and epoxides, like the BA diols, the larger association constants of the bay-region metabolites are reflected in larger polarizabilities and smaller I ionization potentials.' Electronic considerationsof hydrocarbon epoxide reactivities have focused largelyon I electron relaxation effectson activation energies. Generally, increases in I electron delocalization or mobility are accompaniedby decreases in I ionization potential^.^^ For hydrocarbon metabolites, this inverse relationship holds for different epoxides derived from the same parent hydrocarbon.
Figure 7. Plots of polarizabilitiesobtained from 4-3 1G calculationsversus experimental ionization potentials for the highest occupied r orbitals in aromatic hydrocarbons and in metabolites of benz[a]anthracene. The upper panel shows results for thearomatic hydrocarbons benzene, toluene, naphthalene, 1-methylnaphthalene (1-MN), 2-methylnaphthalene (2MN), anthracene, 9-meth ylan t hracene (9- MA), 1,2,3,4-tetrahydro- BA (1,2,3,4-HBA), 9,lO-dimethylanthracene (9,10-DMA), pyrene, and benzo[a]pyrene (BP). The lower panel shows separate plots of polarizabilities versus IP's for the BA diols (DMBAD, EBAD, MBAD, BAD, and BA56D) and the BA epoxides (EBADE, MBADE, BADE, and BAO).
The observed lower I ionizationpotentials,and higher reactivities of bay-regiondiolepoxidesversus K-region epoxides, demonstrated by the BA epoxidesconsidered here, areconsistentwith the inverse relationship between I ionizationpotentials and T delocalization. The IP of BADE is 0.21 eV smaller than that of BAO. The inverse relationship between IPSand delocalization is also consistent with the lower I ionization potentials and higher
2392 The Journal of Physical Chemistry, Vol. 97, No. 10, I993
7.0
7.2
7.1
7.6
8.0
7.8
Fetzer et al.
8.2
IONRATION POTENTIAL (OV)
2OOO
7.0
DUBAD
7.2
7.4
7.6
7.6
8.0
K)NIZ*TK)N POTEHTIAL (OW
Figure 8. Plots of experimental association constants for intercalation into native calf thymus DNA versus experimental ionization potentials for the highest occupied x orbitals in aromatic hydrocarbons and in diols of benz[a]anthracene. The upper panel shows results for naphthalene, 1-methylnaphthalene, 2-methylnaphthalene9 anthracene, 9-methylanthracene, 192,3,4-tetrahydro-BA,and 9,lO-dimethylanthracene. The lower panel shows results for the BA diols, DMBAD, EBAD, MBAD, BAD, and BA56D. Association constants were measured at 23 k 2 OC in 1.0 mM sodium cacodylate at a pH of 7.1. Association constants in the upper panel were measured in 15% methanol; those in the bottom panel were measured without methanol. For anthracene, 1,2,3,4-HBA, 9,10-DMA, DMBAD, EBAD, MBAD, BAD, and BA56D, association constants were taken from refs 1,10,73,and 83. For naphthalene, 1-MN, 2-MN, and 9-MA association constants were measured by using the fluorescence quenching method described in ref 1. For naphthalene, 1-MN, and 2-MN the excitation and emission wavelengths used in the binding measurements were 315 and 350 nm, respectively. For 2-MA the wavelengths were 360 and 420 nm.
reactivities35b of benz[a]anthracene bay-region diolepoxides methylated at the 7- and 12-positions, compared to BADE. In addition to energetic properties such as delocalization energies and ionization potentials, the inherent reactivities of hydrocarbon epoxides are likely to be influenced by local electronic environments at the reaction centers. The activation energies are approximately equal to the energies required to reach states in which the epoxide is protonated and exhibits carbocationic ~haracter.~a~~*J The activation barriers are smaller for reactions in which high T electron mobility permitsa stabilization of positive charge,which developson benzyliccarbon atoms in the transition states. For the benz[a]anthracene epoxides, BADE and BAO, the positive charge develops at the C1 and C5 or C6 atoms, respectively. Sincethe electronsin the highest occupied molecular orbitals (HOMO’S)in hydrocarbon epoxides are the most labile electrons in these molecules,the HOMO’s have a stronginfluence on carbocation transition-state stabilization. The results in Figure 6 suggest that the higher reactivity of the bay-region diolepoxide, BADE, versus that of the K-region epoxide, BAO, may be due not only to the greater r delocalization or smaller IP of BADE but also to the fact that, in BADE, the HOMO has high electron density adjacent to the benzylic carbon atom, C1, which becomes charged in the transition state. The results in Figure 6 further indicate that this favorable electron distribution in the HOMO does not occur for BAO. Here the HOMO has low density at positionsadjacentto the benzyliccarbonatoms, C5 and C6, which are charged in the BAO transition states. This difference between electron distributionsin the HOMOS of bay-region diolepoxides versus K-region epoxides is also exhibited by benzo[a]pyrene. For BP, Figure 10 gives IP’s and orbital diagrams for the bay-region diolepoxide, BPDE, and for
Figure 9. Polarization energy contour maps for anthracene, shown at the top, and 9,1O-DMA, shown at the bottom, obtained from results of 4-3 1G S C F calculations. The maps show contours of equal polarization energy associated with the interaction of a positive point charge (0.5 t u ) at different positions on a grid 1.6 A above the planes containing the carbon atoms of anthracene and 9,lO-DMA. Polarization energies are given in kcal/mol. Solid lines represent even-valued contours. The negative polarization energies shown in the maps represent a favorable energy lowering, which arises via relaxation of the hydrocarbon wave function interacting with the positive charge.
Figure 10. Experimental ionization potentials and theoretical orbital diagrams, obtained from 4-3 1G SCFcalculations, for the benzo[a]pyrene ba y-region diolepoxide, (f)-frans-7,8dihydroxy-anfi-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), and for the K-region epoxide, benzo[a]pyrene-5,6-oxide (BAO). Experimental IPSwere taken from ref 1. Shaded areas denote energy regions of the spectra that contain overlapping bands.
the K-region epoxide, BPO.’ The results for BP in Figure 10 parallel those for BA in Figure 6. In BPDE, the 11 ionization potential is 0.17 eV smaller than in BPO. Furthermore,in BPDE
Genotoxic Benz[u]anthracene Metabolites the HOMO has significant electron density adjacent to the benzylic carbon atom, C10, which becomes charged in the transition state. For BPO, on the other hand, the HOMO again has low density at positionsadjacent to the benzyliccarbon atoms, C4 or CS,which develop charge in the transition states. The photoelectrondata and the HOMO orbital diagrams for the bayregion diolepoxides and the K-region epoxides of benz[u]anthracene and benzo[u]pyrene provide evidence that frontier orbital energiesand electron distributions may strongly influence the relative reactivities of hydrocarbon epoxides. The proposed dependence of reactivity on the detailed structure of the most accessible r orbitals in the hydrocarbon epoxides is consistent with results from investigation^^^,^^ of conformational effects on the hydrolysis of rigid benzylic epoxides. These results suggest that, as the bonding C-O orbitals of the epoxide group overlap more closely with the labile ?r electrons of the aromatic system, carbonium ion stabilization and reactivity increase. Acknowledgment. Support of this work by the American Cancer Society(Grants CN-37 to P.R.L. and CN-22P to R.G.H.), Cray Research, Inc., the Petroleum Research Fund (Grant 26499AC to P.R.L.), and the National Institutes of Health (Grants CA 41432 to P.R.L. and ES 04372 to R.G.H.) is gratefully acknowledged. The Computer Center of the University of Illinois at Chicago, the Cornel1 National Supercomputer Facility, and the National Center for Supercomputing Applications at the University of Illinois, Urbana-Champaign, provided computer access time. References and Notes (1) Urano, S.; Price, H. L.; Fetzer, S. M.; Briedis, A. V.; Milliman, A.; LeBreton, P. R. J . Am. Chem. SOC.1991, 113, 3881. (2) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and Carcinogenesis; Cambridge University Press: Cambridge, England, 1991. (3) Conney, A. H. Cancer Res. 1982,42,4875. (4) (a) Lehr, R. E.; Kumar, S.; Levin, W.; Wood, A. W.; Chang, R. L.; Conney, A. H.; Yagi, H.; Sayer, J. M.; Jerina, D. M. In Polycyclic Hydrocarbons and Carcinogenesis;Harvey, R. G., Ed.; American Chemical Society: Washington, DC, 1985; pp 63-84. (b) Jerina, D. M.; Daly, J. W. In Drug Metabolism from Microbe to Man; Parke, D. V., Smith, R. L., Eds.; Taylor and Francis: London, 1976; pp 13-32. (c) Jerina, D. M.; Lehr, R. E. In Microsomes and Drug Oxidations; Ulbrick, V., Roots, I., Hildebrandt, A., Estabrook, R. W., Eds.; Pergamon Press: Elmsford, NY, 1978; pp 709720. (d) Wood, A. W.; Levin, W.; Chang, R. L.; Yagi, H.; Thakker, D. R.; Lehr, R. E.; Jerina, D. M.; Conney, A. H. In Polynuclear Aromatic Hydrocarbons; Jones, P. W., Leber, P., Eds.; Ann Arbor Science Publishers: Ann Arbor, MI, 1979; pp 531-551. (e) Jerina, D. M.; Lehr, R. E.; Yagi, H.; Hernandez, 0.;Dansette, P. M.; Wislocki, P. G.; Wood, A. W.; Chang, R. L.; Levin, W.; Conney, A. H. In In Vitro Metabolic Activation in Mutagenesis Testing; deSerres, F. J., Fouts, J. R., Bend, J. R., Philpot, R. M., Eds.; Elsevier North-Holland Biomedical Press: Amsterdam, 1976;pp 159-177. (f) Jerina, D. M.; Yagi, H.; Lehr, R. E.; Thakker, D. R.; Schaefer-Ridder. M.; Karle, J. M.; Levin, W.; Wood, A. W.; Chang, R. L.; Conney, A. H. In Polycyclic Hydrocarbons and Cancer; Gelboin, H. V., Ts'o, P. 0. P., Eds.; Academic Press: New York, 1978; Vol. 1, pp 173-188. ( 5 ) LeBreton, P. R. In Polycyclic Hydrocarbons and Carcinogenesis; Harvey, R. G., Ed.; American Chemical Society: Washington, DC, 1985; pp 209-238. (6) MacLeod, M. C.; Mansfield, B. K.; Selkirk, J. K. Carcinogenesis 1982, 3, 1031. (7) Harvey, R. G.; Geacintov, N. E. Acc. Chem. Res. 1988, 21, 66. (8) (a) Geacintov, N. E.; Hibshoosh, H.; Ibanez, V.; Benjamin, M. J.; Harvey, R. G. Biophys. Chem. 1984,20, 121. (b) Shahbaz, M.; Geacintov, N. E.; Harvey, R.G. Biochemistry 1986,25,3290. (c) Kim, M.-H.;Geacintov, N. E.; McQuillen, D. G.; Pope, M.; Harvey, R. G. Carcinogenesis 1986, 7 , 41. (d) Carberry, S. E.; Geacintov, N. E.; Harvey, R. G. Carcinogenesis 1989, IO, 97. (e) Carberry, S. E.; Shahbaz, M.; Geacintov, N. E.; Harvey, R. G . Chem.-Biol. Interact. 1988, 66, 121. (9) MacLeod, M.C.; Selkirk, J. C. Carcinogenesis 1982, 3, 287. (10) Zegar, I. S.; Prakash, A. S.; Harvey, R. G.; LeBreton, P. R. J . Am. Chem. Soc. 1985, 107,7990. (11) Harvey, R. G. Acc. Chem. Res. 1981, 14, 218. (12) (a) Ford, G. P.; Smith, C. T. Inr. J . Quanr. Chem.: Quant. Biol. Symp. 1987,14,57. (b) Ford, G. P.; Smith, C. T. J . Comp. Chem. 1989, I O , 568. (13) Huberman, E.; Sachs, L.; Yang, S. K.; Gelboin, H. V. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 607. (14) (a) Remsen, J.; Jerina, D.; Yagi, H.; Cerutti, P. Biochem. Biophys. Res. Commun. 1977,74,934. (b) Sims, P.; Grover, P. L.; Swaisland, A.; Pal, K.; Hewer, A. Nature 1974,252,326. (c) Grover, P. L.; Hewer, A,; Pal, K.;
The Journal of Physicul Chemistry, Vol. 97, No. 10, 1993 2393 Sims, P. Int. J . Cancer 1976, 18, I. (d) Jeffrey, A. M.; Weinstein, I. B.; Jennette, K. W.; Grzeskowiak, K.; Nakanishi, K.; Harvey, R. G.; Autrup, H.; Harris, C. Nature 1977, 269, 348. (e) Shinohara, K.; Cerutti, P. A. Proc. Narl. Acad. Sci. U.S.A. 1977, 74, 979. (15) (a) Levin, W.; Chang, R. L.; Wood, A. W.; Yagi, H.; Thakker, D. R.; Jerina, D. M.; Conney, A. H. Cancer Res. 1984,44,929. (b) Wood,A. W.;Chang,R. L.;Levin, W.;Yagi,H.;Thakker, D.R.; Jerina, D. M.;Conney, A. H. Biochem. Biophys. Res. Commun. 1977, 77, 1389. (16) Kapitulnik, J.; Wislocki, P. G.; Levin, W.; Yagi, H.; Jerina, D. M.; Conney, A. H. Cancer Res. 1978, 38, 354. (17) (a) Wood, A. W.; Levin, W.; Lu, A. Y. H.; Ryan, D.; West, S. B.; Lehr, R. E.; Schaefer-Ridder, M.; Jerina, D. M.; Conney, A. H. Biochem. Biophys. Res. Commun. 1976, 72,680. (b) Levin, W.; Wood, A. W.; Yagi, H.; Dansette, P. M.;Jerina, D. M.; Conney, A. H. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 243. (c) Kapitulnik, J.; Wislocki, P. G.; Levin, W.; Yagi, H.; Thakker, D. R.; Akagi, H.; Koreeda, M.; Jerina, D. M.; Conney, A. H. Cancer Res. 1978, 38, 2661. (1 8) (a) Oesch, F. In Enzymatic Basis of Detoxification; Jakoby, W. B., Ed.; Academic Press: New York, 1980; Vol. 2, pp 277-290. (b) Bentley, P.; Schmassmann, H.; Sims, P.; Oesch, F. Eur. J . Biochem. 1976, 69, 97. (19) Wood, A. W.; Levin, W.; Lu, A. Y. H.; Yagi, H.; Hernandez, 0.; Jerina, D. M.; Conney, A. H. J . Biol. Chem. 1976, 251, 4882. (20) Meehan, T.; Bond, D. M. Proc. Narl. Acad. Sci. U.S.A. 1984, 81, 2635. (21) Prakash, A. S.; Harvey, R. G.; LeBreton, P. R. In Polynuclear Aromatic Hydrocarbons: A Decade of Progress; Cooke, M.,Dennis, A. J., Eds.; Battelle Press: Columbus, OH, 1988; pp 699-710. (22) MacLeod, M. C.; Zachary, K. Chem.-Bioi. Interactions 1985, 54, 45. (23) MacLeod, M. C.; Zachary, K. L. Carcinogenesis 1985,6, 147. (24) Geacintov,N. E.;Yoshida,H.;Ibanez,V.;Harvey,R.G.Biochemistry 1982, 21, 1864. (25) Geacintov, N. E.; Shahbaz, M.; Ibanez, V.; Moussaoui, K.; Harvey, R. G. Biochemistry 1988, 27, 8380. (26) Gupta, S. C.; Pohl, T. M.;Friedman, S. L.; Whalen, D. L.; Yagi, H.; Jerina, D. M. J . Am. Chem. SOC.1982, 104, 3101. (27) Michaud, D. P.; Gupta, S. C.; Whalen, D. L.; Sayer, J. M.; Jerina, D. M. Chem.-Biol.Interact. 1983, 44, 41. (28) Murray, A. W.; Grover, P. L.; Sims, P. Chem.-Biol. Interact. 1976, 13, 57. (29) (a) Huggins, C. B.; Pataki, J.; Harvey, R. G. Proc. Natl. Acad. Sci. U.S.A.1967,58,2253. (b) Pataki, J.; Huggins, C. Cancer Res. 1969,29,506. (30) Akiyama, 1.; Li, K. C.; LeBreton, P. R.; Fu, P. P.; Harvey, R. G. J . Phys. Chem. 1979, 83, 2997. (31) Harvey, R. G.; Sukumaran, K. B. Tetrahedron Lett. 1977, 2387. (32) Lee, H. H.; Harvey, R. G. J. Org. Chem. 1979, 44, 4948. (33) Glatt, H.; Harvey, R. G.; Phillips, D.; Hewer, A,; Grover, P. L. Cancer Res. 1989, 49, 1778. (34) Harvey, R. G.;Cortez, C.; Sugiyama, T.; Ito, Y.; Sawyer, T. W.; DiGiovanni, J. J . Med. Chem. 1988, 31, 154. (35) (a) Sukumaran, K. B.; Harvey, R. G. J. Org. Chem. 1980,45,4407. (b) Lee, H.; Harvey, R. G. J . Org. Chem. 1986, 51, 3502. (36) Harvey, R. G.; Fu, P. P. In Polycyclic Hydrocarbons and Cancer; Gelboin, H. V., T'so, P. 0. P., Eds.; Academic Press: New York, 1981; Vol. 1, pp 133-165. (37) Koopmans, T. Physica 1933, I , 104. (38) Lindholm, E.; Asbrink, L. Molecular Orbitals and their Energies, Studied by the Semiemperical HAM Method Springer-Verlag: New York, 1985. (39) Ditchfield, R.; Henre, W. J.; Pople, J. A. J . Chem. Phys. 1971, 54, 724. (40) Gaussian 90: Frisch, M. J.; Head-Gordon, M.; Trucks, G. W.; Foresman, J. B.; Schlegel, H. B.; Raghavachari, K.; Robb, M.; Binkley, J. S.; Gonzalez, C.; Defrees, D. J.; Fox, D. J.; Whiteside, R. A.;Seeger, R.; Melius, C. F.;Baker, J.;Martin,R.L.;Kahn,L.R.;Stewart, J. J. P.;Topiol,S.;Pople, J. A. Gaussian, Inc.: Pittsburgh, PA, 1990. (41) (a) Pulay, P.; Meyer, W. J. Chem. Phys. 1972, 71, 2150. (b) Komornicki, A.; Jaffe, R. L. Ibid. 1979, 71, 2150. (42) Cox, E. G.; Cruickshank, D. W.; Smith, J. A. S . Nature (London) 1955, 175, 766. (43) Keidel, F. A. Annu. Reu. Phys. Chem. 1953, 4 , 236. (44) Abrahams, S. C.; Robertson, J. M. Acta Crystallogr. 1949, 2, 233. (45) Lipowski, J.; Sgarabotto, P.; Andreeti, G. Acta Crystallogr. 1980, 836, 51. (46) Mason, R. Acta Crystallogr. 1964, 17, 541. (47) (a) Cox, P.; Sim, G. Acta Crystallogr. 1979,835,404. (b) Iball, J. Acta Crystallogr. 1974, 830, 2203. (48) Robertson, J. M.; White, J. G . Acta Crystallogr. 1947, 358. (49) Neidle, S.; Subbian, A.; Cooper, C. S . ; Riberio, 0. Carcinogenesis 1980, 1, 249. (50) Glusker, J. P.; Zacharias, D. E.; Carrell, H. L.; Fu, P. P.; Harvey, R. G. Cancer Res. 1976, 36, 3951. (51) Walker, N.; Briant. C.; Jones, D.; Shaw, J. Acta Crystallogr. 1986, C42, 1392. (52) Beland, F. A,; Melchior, W. B., Jr.; Klimkowski, V. J.; Scarsdale. J. N.; Van Alsenoy, C.; Schafer, L. Carcinogenesis 1984, 5 , 1097. (53) Glusker, J. P.;Carrell, H. L.; Zacharias, D. E.;Harvey, R.G. Cancer Biochem. Biophys. 1974, 36, 3951. (54) Bowen, H. J. M.; Donohue, J.; Jenkin. D.G.;Kennard,O.; Wheatley, P. J.; Whiffen, D. H. In Tables of Interatomic Distances and Configuration
2394 The Journal of Physical Chemistry, Vol. 97, No. 10, 1993
Fetzer et al.
in Molecules and Ions; Sutton. L. E., Jenkin, D. G., Mitchell, A. D., Cross, (78) Schuyler, J.; Blom, L.; van Krevelerf, D. Trans. Faraday Soc. 1953, L. C., Eds.; The Chemical Society: London, 1958;pp M205, M214, M238, 49, 1391. (79)White, C. M.; Schmidt, C. E. Fuel 1987,66,1030. S13. ( 5 5 ) Dewar, M.; Zoebisch, E.; Healy, E. J . Am. Chem. Soc. 1985,107, (80) Clar, E. Tetrahedron 1975,31, 2263. (81) Klasinc, L.; KovaE, B.; Giisten, H. Pure Appl. Chem. 1983.55,289. 3902. (56) Clark, T. A Handbook of Computational Chemistry; John Wiley: (82)Lamparczyk, H.; Ochocka, R. J. Chromatographia 1987,23, 337. New York, 1985;p 267. (83) Shahbaz, M.; Harvey, R. G.; Prakash. A. S.; Boal, T. R.; Zegar, I. (57) Arnott, S.;Chandrasekaran, R.; Selsing, E. In Structure and S.; LeBreton, P. R. Biochem. Biophys. Res. Commun. 1983,112, 1. In the Conformation of Nucleic Acids and Protein-Nucleic Acid Interactions; reproduction of the photoelectron spectrum of 1,2,3,4-tetrahydrobenz[a]Sundaralingam, M., Rao, S. T., Eds.;University Park Press: Baltimore, 1975; anthracene given in Figure 4 of this reference, the label for the first ionization potential was deleted. However, the value of the IP read from the spectrum pp 571-597. is equal to the value listed here in Table I. (58) Tasaki, K.; Yang, X.;Urano, S.; Fetzer, S.; LeBreton, P. R. J . Am. (84) Miller, K. J.; Savchik, J. A. J . Am. Chem. Soc. 1979. 101,7206. Chem. Soc. 1990, 112,538. (85) Levine. I. N. Physical Chemistry; McGraw Hill: New York, 1978; (59) (a) Schweig. A.; Theil, W. Chem. Phys. Lett. 1973,21, 54. (b) Corderman, R. R.; LeBreton, P. R.; Buttrill, S. E., Jr.; Williamson, A. D.; p 729. (86)Paulius, D. E.;Prakash, A. S.;Harvey, R. G.; Abramovich, M.; Beauchamp, J. L. J . Chem. Phys. 1976,65,4929.(c) McAlduff, E.J.; Houk, K. N. Can. J. Chem. 1977,55, 318. LeBreton, P. R. In Polynuclear Aromatic Hydrocarbons: Chemistry, (60)Padva, A.; ODonnell, T. J.; LeBreton, P. R. Chem. Phys. Lett. 1976, Characterization, and Carcinogenesis; Cooke, M., Dennis, A. J., Eds.; 41,218. Battelle: Columbus, OH, 1986;pp 745-754. (61)Lin,J.-H.;Yu,C.;Peng,S.;Akiyama,I.;Li,K.;Lee,L.-K.;LeBreton,(87) Miller, K. J.; Taylor, E. R.; Dommen, J. In Polycyclic Hydrocarbons P. R. J. Am. Chem. Soc. 1980, 102,4627. and Carcinogenesis; Harvey, R. G., Ed.; American Chemical Society: (62) Lin, J.-H.; LeBreton, P. R.;Shipman, L. L. J . Phys. Chem. 1980,84, Washington, DC, 1985;pp 239-288. 642. (88) Klopman, G.;Grinberg, H.; Hopfinger, A. J. J . Theor. Biol. 1979, (63) MacLeod, M. C. J. Theor. Biol. 1990, 142, 113. 79, 355. (64) Geacintov, N. E. Carcinogenesis 1986,7 , 759. (89) Jerina, D. M.; Sayer, J. M.; Yagi, H.; Croisy-Delcy, M.; Ittah, Y.; Thakker, D. R.; Wood, A. W.; Chang, R. L.; Levin, W.; Conney, A. H. In (65) Islam, N. B.; Whalen, D. L.; Yagi, H.; Jerina, D. M. J. Am. Chem. Soc. 1987,109,2108. Adv. Exp. Med. and Biol.: Biological Reactive Intermediates, Part 2A: (66) Bunton, C. A,; Rubin, R. J. J . Am. Chem. SOC.1976,98,4236. Chemical Mechanisms and Biological Effects;Snyder, R., Parke, D. V.,Kocsis, (67) Bunton, C. A.; Romsted, L. S.; Smith, H. J. J . Org. Chem. 1978,43, J. J., Jollow, D. J., Gibson, C. G., Witmer, C. M., Eds.; Plenum Press: New York. 1982: Vol. 136. DD 501-523. 4299. (68) Lamm, G.; Pack,G. R. Proc. Narl. Acad.Sci. U.S.A.1990,87,9033. (90) Dickerson, R: E.;Drew, H. R.; Conner, B. N.; Wing, R. M.; Fratini, (69)Bunton, C. A.; Savelli, G. Ado. Org. Chem. 1986,22,213. A. F.; Kopka, M. L. Science 1981,216, 171. (70) MacCleod, M.;Smith, B.; McClay, J. J . Biol. Chem. 1987,262, (91) Osborne, M. R.;Connell, J. R.; Venitt,S.;Crofton-S1eigh.C.; Brookes, 1081. P.; DiGiovanni, J.; Pataki, J.; Harvey. R. G. In The Role of Chemicals and (71) Shimer,G. H., Jr.; Wolfe,A. R.; Meehan,T. Biochemistry 1988,27, Radiation in the Etiology of Cancer;Huberman, E., Ed.; Raven Press: New 7960. York, 1985;pp 449464. (72)Abramovich, M.;Prakash,A. B.; Harvey,R. G.; Zegar, I.S.;LeBreton, (92) (a) Weinstein, H.; Chou, P.; Kang, S.; Johnson, C. L.; Green, J. P. P. R. Chem.-Biol. Interact. 1985,55, 39. Inr. J . Quanr. Chem.: Quant. Biol. Symp. 1976,3, 135. (b) Weinstein, H.; (73)Urano, S.; Fetzer, S.; Harvey, R. G.;Tasaki, K.; LeBreton, P. R. Osman, R. Ibid. 1977,4,253. Biochem. Biophys. Commun. 1988, 154,789. (93)Sayer, J. M.; Lehr, R. E.; Wahlen, D. L.; Yagi, H.; Jerina, D. M. (74)Saenger, W. Principles of Nucleic Acid Structure; Springer-Verlag: Tetrahedron Lett. 1982,23,4431. New York, 1984;pp 137-140. (94) Cotton, F. A. Chemical Applicationsof Group Theory, 3rded.; Wiley (75) Bogaard, M. P.; Buckingham, A. D.; Corfield, M. G.;Dunmur, D. Interscience: New York. 1990 OD 148-158. A.; White, A. H. Chem. Phys. Lett. 1972,12, 558. (95) Whalen, D. L.; Ross, A:M.; Yagi, H.; Karle, J. M.; Jerina, D. M. (76) Kimura, K.; Katsumata, S.; Achiba, Y.; Yamazaki, T.; Iwata, S . J . Am. Chem. SOC.1978, 100,5218. Handbook of HeI PhotoelectronSpecrraof Fundamental Organic Molecules; (96) Sayer, J. M.; Yagi, H.; Silverton, J. V.; Friedman, S. L.; Whalen, D. Halsted Press: New York, !981;pp 188, 189. L.; Jerina, D. M. J. Am. Chem. Soc. 1982,104, 1972. (77)Sanyal, N.; Ahmed, P.; Dixit, L. J. Phys. Chem. 1973,77, 2552.
