matic reaction with glutathione on other cellular nucleophiles.
Although considerable effort has been expended on investigating the properties of hydrocarbon metabohites, thenature of their chemical reactions leading to carcinogenesisis largely unknown. Since more precise structural information may be expected to contribute to the elucidation of themechanism of induction of cancer by certain polycyclicaromatic hydrocarbons, we have undertaken investigationsof the structures of selected metabolites of such cancinogens by means of X-ray crystallographic analyses. We neport here the crystallographic study of the structure of theK-region oxide of BP3, BP-4,5-oxide. The arene oxides ofBP are of particular interest due to the ubiquitous presence
of this carcinogen in the human environment (7). BP-4,5-oxide has been detected as a metabohite of BP (13, 33) andhas been reported to be highly mutagenic in Salmonellatyphimurium and in Chinese hamster V79 cells (39).
MATERIALS AND METHODS
The compound to be studied, BP-4,5-oxide, was preparedas described by Goh and Harvey (11). Crystals were grown,and a structural analysis was then done by X-ray crystallographic techniques. Details of the procedure are describedbelow.
Crystal Data. BP-4,5-oxide, C2OHI2O,monochinic spacegroupP2,/n,a = 17.341(5),b =4.095(1),c = 17.847(5)A;13= 90.93(2)°, V = 1267.3(5) A', z = 4, x = 1 .5418 A, D@ =
were obtained with CuKa-monochnomated radiation with anautomated 4-circle diffractometer. The 0-20 variable scantechnique was used to a maximum value of sin 0/A of 0.606A-i . Of 2412 independent reflections measured, 1333 wereabove the observational threshold of 2o-(/), where o-(I) wasderived from counting statistics. Values of o-(F)were determined from the equation
o-(F) (F/2){[i@(l)/P] + 62}J12
where 8 is an instrumental uncertainty (6 = 0.020) determined from the variation in measured intensities for someperiodically scanned standard reflections. The crystal size
3 The abbreviations used are: BP, benzo(a)pyrene; BP-4,5-oxide,
benzo(a)pyrene-4,5-oxide; DMBA, 7,12-dimethylbenz(a)anthracefle; DMBA5,6-oxide, dimethylbenz(a)anthracene 5,6-oxide. R value = 1(1F01—IF@II/1IF0Iwhere F0 is an observed structure factor and F@is a calculated structurefactor.
SUMMARY
An X-ray crystallographic study of benzo(a)pyrene 4,5-oxide, a metabohite of the carcinogen benzo(a)pyrene (BP),has given information on the geometry of this molecule. Thecarbon skeleton of BP itself has been shown by others to benearly planar; the plananity of the carbon skeleton hasbeen shown by this work to be perturbed very little byepoxidation of the 4,5-double bond. Epoxidation has, however, increased the double bond character of C-ii—C-12,C-9-—C-10,and C-7—C-8.The hydrogen atom on C-3 pointsdirectly toward the oxygen atom of another molecule. ThisC—H . . . 0 interaction, although weak, suggests that C-3might be slightly acidic. An analysis of the experimentallydetermined bond lengths indicates that, after the highlyreactive epoxide ring, the most reactive positions are at C-i,C-6, C-7, C-li, and C-12. The oxide ring of BP, unlike that
for the K-region oxide of 7,i2-dimethylbenz(a)anthnacene,is symmetrical (with C—Odistances equivalent within expenimental error). The C—Cdistances are longer than thosefound in most oxides, including those in 7,12-dimethylbenz(a)anthracene-5,6-oxide. Thus it has been shown thatthe oxide rings of the K-region oxides of the two potentcarcinogens BP and 7,12-dimethylbenz(a)anthracene arenot similar in dimensions.
INTRODUCTION
Anene oxides have been postulated as the metabolicallyactivated forms of carcinogenic hydrocarbons (6), and evidence has been presented to support this theory. Thus theK-region2 arene oxides have been shown to be more activethan the parent hydrocarbons in the transformation ofmammalian cells in culture (15, 17, 26), to be more highlymutagenic (1) than either the parent hydrocarbons (16) onthe non-K-region oxides (38), and to bind covalently tonucleic acids and proteinsin vivo (2, 5, 12, 25). On the otherhand, the tumonigenicity of these derivatives has beenshown to be lower than that of the parent hydrocarbons(34), possibly as a consequence of ready conversion tohighly reactive forms and to detoxification through enzy
1 This research was supported by USPHS Grants CA-10925, CA-06927, CA
11968, and RR-05539 from the NIH; BC-132 from the American CancerSociety; AG-370 from the National Science Foundation; and an appropriationfrom the Commonwealth of Pennsylvania.
2 The K-region in a polycyclic ring system is defined as a bond, such as the
9,10-bond of phenanthrene, which undergoes addition reactions in the sameway that olefins do.
Received April 27, 1976; accepted July 22, 1976.
3951NOVEMBER 1976
Molecular Structure of Benzo(a)pyrene 4,5-Oxide1
JennyP.Glusker,DavidE.Zacharias,H.L.Carrell,PeterP.Fu,andRonaldG.HarveyTheInstitute for CancerResearch,TheFoxChaseCancerCenter,Philadelphia,Pennsylvania19111(J. P. G., 0. E.Z., H. L. C.),and BenMayLaboratoryforCancer Research, The University of Chicago, Chicago, Illinois 60637 (P. P. F., R. G. H.J
was 0.1 x 0.1 x 0.4 mm. The density of the crystals wasmeasured in a mixture of carbon tetrachlonide and methylene dichlonide. No correction for absorption was applied,and the intensity fall-off, shown by measurements of standand reflections, was negligible as a function of time. Lorentzand polarization corrections were applied to the intensitiesto obtain values for structure amplitudes.
Structure Refinement. The structure was solved from thePatterson map. Isotropic, then anisotropic, full-matrix leastsquares methods were used to refine the structure. Allhydrogen atoms were located from a difference map calcuhated at the stage at which all heavier atoms had beenrefined anisotropically to convergence (R = 0.114). Thepeaks selected from this map lay in the range 1.07 to 1.24e/[email protected] hydrogen atoms were then refined isotnopically,together with heavier atoms (which were refined anisotropically). The final residual is R = 0.065, and the weightedresidual is 0.069. The final difference map was featurelessand contained no peaks higher than 0.17 e/A@.
Computer programs used were UCLALS4,4 modified by H.L. Carrell; the CRYSNET package (4); and other programswritten in the Institute for Cancer Research laboratory. Thequantity minimized in the least-squares calculation was
@w{IIF0I—IF@II}2.The weights of the reflections, w, during therefinement were 1/[o-9F)J with zero weight for those neflections below the threshold value. The atomic scattering factons used for oxygen and carbon atoms (21) and for hydnogen atoms (36) are listed in the literature.
Positional parameters are listed in Table 1. A list of observed and calculated structure factors is available from theEditorial Office or the authors on request.
RESULTS
The carbon skeleton of BP-4,5-oxide is approximatelyplanar with the oxide ring inclined at an angle of 103°to it(Chart ia). Some views of the molecule are shown in Chart 1(a to c). The maximumangulardeviationbetweentheplanes through each 6-membened ring is 5.14°(Table 2).The root mean square deviation of all carbon atoms fromthe least-squares plane through the ring system (excludingthe oxygen atom) is 0.05 A. The maximum deviations are0.1 1 A for C-12, 0.09 A for C-3, and —0.06A for C-li and C-16. The approximate plananity of the carbon skeletonclosely resembles the planar ring system of phenanthrene9,10-oxide. This contrasts with the twisted geometry ofDMBA-5,6-oxide (9).
The structure of BP was previously determined by Iball etal. (19, 20) using crystallographic techniques. The majordifferences resulting from epoxidation of BP are a shortening of the localized double bonds C-11——C-12,C-9—C-10,and C-7—C-8 to 1.338, 1.345, and 1.352 A (from 1.352,1.364, and 1.374 A), and a lengthening of the bonds C-S—C-17, C-4—C-15, and C-4—C-5that lie near the oxide ring.
4 P. K. Gantzel, R. A. Sparks, A. E. Long, and K. N. Trueblood. Full Matrix
Least Squares Program. UCLALS4 Program in Fortran IV.
These and other changes are illustrated in Chart 2. In bothBP and BP-4,5-oxide, the ring systems are fairly flat (exclud
ing the oxide). The maximum deviation from the leastsquares plane through the molecule of BP is 0.04 A for C-2and C-i 1. In the case of the oxide, BP-4,5-oxide, thedeviation is slightly larger, i.e., 0.11 A for C-2. Thus epoxidation has had little effect on the general conformation ofthe carbon ring system.
The interatomic distances and angles of the moleculeare shown in Chart 3. The oxide ring is distinguished bymuch longer C—Obonds (1.478 and 1.481 A) than those ineither the DMBA or phenanthrene K-oxides (1.445 and1.457, and 1.461 and 1.459 A, respectively) (9). Moreover,although the C—Obonds are almost identical, the oxidering is not entirely symmetrical , since the external C—C—Oangles are 116.3°for C-i5—C-4—Oand ii4.9° for C-17—C-5—O.The values of such angles for the symmetrical phenanthrene 9,10-oxide are 115.5°,whereas for DMBA-5,6-oxide the analogous values are 117.9°and 114.3°.The unsubstituted K-region bond between C-i i and C-i 2 is 1.338 Along, nearly a pure double bond. Other short bonds are C-9—C-b and C-7—C-8with bond distances of 1.345 and1.352 A, respectively.
Free valences (31) may be calculated from experimentalbond lengths. This is done (10) by summing the ir bondorders around each atom and noting the difference fromthat predicted theoretically. These free valences or unsaturation indices give an approximate measure of the susceptibihity of any atom to attack. Such studies of experimentalbond orders indicate that, after the highly reactive oxidering, the most reactive positions are atoms C-i and C-6,then C-7, C-il, and C-i2.
The crystal packing, viewed down the@ axis (which isonly 4.1 A long, is shown in Chart 4. The surroundings of anisolated molecule are shown in Chart 5. Inspection of thelatter reveals that the ring bearing the oxide function (RingC―) lies under the ring with the 2nd K-region (Ring E). The
separation between the planes through the aromatic ringsystems is 3.56 A, and the oxygen atom is directed awayfrom the overlapping carbon ring system. For example, inChart 5, the oxygen atoms (in Rings F and F―)lie below theplane of the rest of the molecules when viewed from abovethe plane of the paper. If the reverse were true and theoxygen atoms lay above the plane, an unreasonably closeapproach to the next molecule would result, e.g., the oxygen atom on Ring F―would lie too close to Ring C.
The environment of the oxygen atom of 1 molecule mayprovide clues as to any change distribution in the rest of themolecule. It is found that there are 3 close approachesbetween the oxide oxygen atom and the ring systems ofother molecules. These are listed in Table 3 and are illustrated in Chart 5 by broken lines. Some interaction betweenthe slightly negatively charged oxygen atom of 1 moleculeand C-4 and C-S of another molecule might be expectedfrom the electron-withdrawing properties of the oxygenatom, which would affect these 2 carbon atoms more thanany others. This effect would be anticipated to aid thestacking of molecules. This is the situation that is found inthis study. The additional interaction of the oxygen atomwith C(3―)is of interest because the C—H. . . 0 interaction
is nearly linear (see Table 3), i.e., the hydrogen atom on C-3―points directly toward the oxygen atom of the oxidering. The distances (Table 3) are near those of van den Waalscontacts (C . . . 0 = 3.1 A; H . . . 0 = 2.4 to 2.6 A) so that theinteraction is weak and longer than distances listed forC—H . . . 0 hydrogen bonds (37). However, this situationimplies that there is a slightly acidic hydrogen atom on C-3,which, in turn, implies that there may be some residualpositive charge on C-3.
DISCUSSION
Three-dimensional structure determinations of the K-negion oxides of BP, DMBA, and phenanthmene reveal that thehydrocarbon ring systems of both BP-4,5-oxide and phenanthnene 9,10-oxide are essentially planar, whereas that ofDMBA-S,6-oxide is nonplanar with an angle of 35°betweenthe outer rings. The nonplananity of both DMBA and its 5,6-
oxide (9, 10, 18) has been shown to be primarily a consequence of stenic repulsion between the 12-methyl group anda hydrogen atom of the [a] ring. Thus the hydrocarbon ringsystems of K-region oxides of polycychic hydrocarbonswhich lack such special stenic features would , in general , beexpected to be planar. It appears likely, however, in view ofthe nonplananity of the hydrocarbon ring system of DMBAand its known derivatives (9) and the planarity of the hydnocarbon ring system of BP, that plananity is not an importantfactor in the cancinogenicity of polycyclic aromatic hydnocarbons (10).
The external angles about the oxide rings of the 2 carcinogen derivatives have been found to be less symmetricalthan those of phenanthrene oxide. This supports our previously stated postulate (9) that the K-region oxides of carcinogens differ from their inactive counterparts by a polanization of the oxide functions, thereby leading to their enhanced reactivity with cellular nucleophiles. This is inagreement with the hypothesis of Miller and Miller (28) that
Angles between p1anesin themoleculeA:B1.16°B:D5.14°C:alI0.60°A:C1.32B:E2.37D:E3.00A:D3.98B:F102.80D:F102.06A:E1.26B:all1.94D:all3.34A:F102.75C:D2.76E:F103.24A:aII0.84C:E0.38E:alI0.44B:C2.47C:F102.92F:alI102.12
Root-mean-square deviations of carbon atoms from the leastsquaresplanesthrough each ring (inA)A.0.0030
E.0.0072B.0.0037F.0.0000C.0.0i57
All rings0.0478D.0.0082
J. P. Gluskeretal.
the active forms of most carcinogens are electnophileswhich initiate tumor formation through covalent interactionwith either nucleic acids on other cellular macmomoleculartargets. However, the amount of asymmetry in BP-4,5-oxideis very much less than that found for DMBA-5,6-oxide. It isfound that DMBA-5,6-oxide reacts preferentially with guanine residues in nucleic acids to afford equal amounts ofthe guanine-hydrocarbon adducts. These anise from neaction at both oxide ring carbon atoms (5, 22, 23). In contrastto these results, reactions of DMBA-5,6-oxide with simplenucleophiles (3) on acid-catalyzed solvolysis (14, 24, 29)proceed via preferential opening of the C-6—Obond. In asimilar reaction with model nucleophiles (3), BP-4,5-oxidefurnished, unlike DMBA-S,6-oxide, essentially equal quantities of the products of reaction at the 4- and 5-positions. Thereactions with simple nucleophiles were conducted underconditions favoring an SN2mechanism of ring opening, i.e.,high pH and a potent nucleophile, whereas the reactionswith nucleic acids were carried out near neutral pH, andreaction occurred principally on the 2-amino group of guanosine, a relatively weak nucleophihic center. These resultssuggest a greaten likelihood of an SN, process in this case.Thus any effect that might favor enhanced SN, reactivitymay be important in the interaction of these compoundswith nucleic acids. It is, however, premature to draw anyfirm conclusion regarding the relationship between structune and biological activity of the K-oxides. Further structunal investigations will be required to determine whetherasymmetry of the oxide ring is indeed a characteristic of theoxides derived from carcinogenic hydrocarbons.
Since both BP and DMBA are carcinogenic, a comparisonof the K-region oxides of the 2 compounds was made inorder to determine the region of greatest similarity. Such aregionisfound inthe outerringportionof regionC-6 to C-10 in BP-4,5-oxide, as judged from a comparison of bondlengths. A similar comparison for BP and DMBA showssimilarities across the K-region (C-iS to C-i7) and in theouter ring (C-7 to C-i9). The outer ring is the site of hydnoxylation and epoxidation to give a 7,8-dihydro-7,8-dihydroxybenzo(a)pynene-9,1 0-oxide (35), a postulated intermediatein the carcinogenic process by BP. Our comparison of BPand BP-4,5-oxide indicates that any puckering in the outerring (positions 7 to 10) of the diol epoxide will be causedmainly by the saturation (on diol formation) at the 7- and 8-positions and not by epoxidation at the 9- and 10-positions.
An analysis of the X-ray structural studies on epoxidesrevealed that several had been studied in great detail, including 3 antileukemic agents, mezerein (30), tniptolide (8),and tnipdiohide (8). In addition, good data are available on
I .la
lb
ic
Chart 1. Some views of the molecular structure of BP-4,5-oxide. •,oxygen atoms. a, view along the plane of the carbon skeleton; b, view onto theplane of the carbon skeleton; c, general view of the molecule.
Chart 3. Bond distances and interbond angles for BP-4,5-oxide. Estimated standard deviations are 0.004 to 0.006 A for bond distances except for thoseinvolving hydrogen atoms ( 0) when they are 0.04 to 0.05 A. Estimated standard deviations for bond angles are 0.2-0.3°for angles involving carbon andoxygen atoms and 2-3°if hydrogen atoms are involved.
C—
a
Chart 5. The surroundings of 1 molecule (black bonds and atoms). Oxygen atoms are stippled. A complete view of 2 molecules separated by a@translation is shown, and the overlap of rings is indicated by shading.Portions of 2 other molecules (see Table 3) are also shown.
bonds were 1.44 A, Ring C—Cbonds were 1.47 A, and theaverage external 0—C—Cangle was 115.7°.The longerC—O bonds in BP-4,5-oxide (1 .48 A) may imply a greaterease of C—Obond breaking. The antileukemic agents have,in some cases, hydroxyl groups on carbon atoms adjacentto the epoxide rings. The conformations axia cis (triptolide, tripdiohide, with 0 . . . 0 distances of 2.75 to 2.78 A),equatorial cis (diepoxycyclohexane, 0 . . . 0 = 3.01 A), andequatorial trans (tniptohide, tnipdiohide, mezerein 0 . . . 0 =3.64 to 3.68 A) are illustrated in Chart 6. In the case of tripdiohide, the hydroxyl group forms a hydrogen bond to an
1Chart 4. Packing in 1 unit cell of the crystal. The view is along the@ axis
(4.095 A). - - - -, interaction between C-3 and 0. Sf, 2 atoms, 1 unit cell (in @)apart. Thus a continuous spiral up the@ axis and throughout the crystal isformed.
tetracyanoethylene oxide (27) (including a neutron diffraction study for comparison) and a diepoxycyclohexane (32).In these and in the K-region oxides, the average Ring C—O
I. @/2 X, @/2+ y, @/2—z (Chant5)II.@/2 X, y —@/2,@/2 Z (also Chart5)III.
x, y —1, z
J. P. Glusker et a!.
epoxide oxygen atom in another molecule. No intramolecular hydrogen bond is formed. However, the 14f3-hydnoxylgroup (0-4) is only 3.13 to 3.15 A from the epoxide oxygenatom (0-6)(32).The relationshipoftniptohideand tripdiolide
Table3
to the diol epoxide, suggested as the active metabolic intermediate in carcinogenesis by BP (35), has been pointed out(40).
In summary, this structural study has yielded the followinginformationon BP-4,5-oxide,a metabohiteofthe cancinogen BP.
The C—Obond lengths of BP-4,5-oxide are longer thanthose reported for the oxides of DMBA on phenanthrene,or, indeed, for any other epoxides studied to date.
As shown by lball et a!. (19), the carbon skeleton of BP isfairly planar. The work reported here shows that the planarity of the carbon skeleton of BP has been perturbed verylittle by epoxidation of the 4,5-double bond to give BP4,5-oxide.
The atom C-3 of BP-4,S-oxide may be slightly acidic, sincea linear C—H . . . 0 interaction is formed with the oxygen
14. Harvey,R.G.,Goh,S.H.,andCortez,C. “K-Region―OxidesandRelatedOxidized Metabohites of Carcinogenic Aromatic Hydrocarbons. J. Am.Chem. Soc.. 97: 3468-3479, 1975.
15. Heidelberger, C. Chemical Oncogenesis in Culture. Advan. Cancer Res.,20:317-366,1974.
16. Huberman, E., Aspires, L., Heidelberger, C., Grover, P. L., and Sims, P.Mutagenicity to Mammalian Cells of Epoxides and Other Derivatives ofPolycyclic Hydrocarbons. Proc. NatI. Acad. Sci. U.S., 68: 3195-3199.1971.
17. Huberman,E.,Kuroki,T., Marquardt,H.,Selkirk,J. K., Heidelberger,C.,Grover, P. L. , and Sims, P. Transformation of Hamster Cells by Epoxidesand Other Derivativesof PolycychicHydrocarbons.Cancer Res., 32:1391-1396, 1972.
18. Iball, J. A Refinement of the Structure of 9:10-Dimethyl-1 :2-benzanthracane. Nature, 201: 916-917, 1964.
19. Iball, J., Scrimgeour,S. N., and Young, D. W. 3,4-Benzopyrene(a NewRefinement). Acta Cryst., B32: 328-330, 1976.
20. IbahI,J., and Young, D. W. Structure of 3:4-Benzpyrene.Nature, 177:985-986, 1956.
22. Jeffrey, A., Blobstein, 5., Weinstein, I. B., and Harvey, A. G. HighPressure Liquid Chromatography of Carcinogen-Nucleoside Conjugates: Separation of 7,12-Dimethylbenzanthracene Derivatives. Anal.Biochem., 73: 378-385, 1976.
23. Jeffrey,A. M., Blobstein,S. H., Weinstein, I.B., Beland, F. A., andHarvey, R. G. Structure of 7,12-Dimethylbenz[a]anthracene-GuanosineAdducts. Proc. NatI. Acad. Sci. U. S., 73: 2311-2315, 1976.
24. Keller, J. W.. Heidelberger, C. Polycyclic K-Region Arene Oxides: Productsand Kineticsof Solvolysis.J. Am. Chem. Soc. ,98: 2328-2336, 1976.
25. Kuroki, T., Huberman,E., Marquardt,H., Selkirk, J., Heidelberger,C.,Grover, P., and Sims, P. Binding of K-Region Epoxides and Other Denyatives of Benz(a]anthracene and Dibenzfa,h]anthracene to DNA, RNA,and Proteins of Transformable Cells. Chem.-BioI. Interactions, 4: 389-397,1971-1972.
26. Marquandt,H., Kuroki, T., Hubenman,E., Selkirk, J. K., Heidelberger, C.,Grover, P. L., and Sims, P. Malignant Transformation of Cells Derivedfrom Mouse Prostate by Epoxides and Other Derivatives of PolycyclicHydrocarbons. Cancer Res., 32: 716-720, 1972.
27. Matthews,D.A., Swanson,J., Mueller,M. H.,andStucky,G.D.Bondingand ValenceElectron Distribution in Molecules.An x-ray and NeutronDiffraction Study of the Crystal and Molecular Structure of Tetracyanoethylene Oxide. J. Am. Chem. Soc., 93: 5945-5953, 1971.
28. Miller, E. C., and Miller, J. A. in: H. Busch (ed), MolecularBiology ofCancer, pp. 377-402. New York: Academic Press, Inc. , 1974.
29. Newman, M. S., and Olson, D. R. A New Hypothesis Concerning theReactiveSpecies in Carcinogenesisby 7,12-Dimethylbenz[a]anthracene.The 5-Hydroxy-7,12-dimethylbenz[a]anthracene-7,12-Dimethylbenz[a]-anthracene-5(5H)-one Equilibrium. J. Am. Chem. Soc., 96: 6207-6208,1974.
30. Nyborg, J., and LaCour, T. X-ray Diffraction Study of Molecular Structureand Conformation of Mezerein. Nature, 257: 824-825, 1975.
31. Pullman, B., and Pullman, A. Quantum Biochemistry, Chap. 3, p. 84;Chap.4, p. 155-181. NewYork: lntersciencePublishers,1963.
33. Selkirk,J. K., Croy,A. G.,andGelboin,H.V. IsolationandCharacterization of Benzo(a]pyrene-4,5-Epoxide as a Metabolite of Benzo[ajpyrene.Arch. Biochem. Biophys., 168: 322-326, 1975.
34. Sims,P.,andGrover,P.L. Epoxidesin PolycychicAromaticHydrocarbonMetabolism and Carcinogenesis. Mvan. Cancer Res., 20: 165-274, 1974.
35. Sims, P., Grover, P. L., Swaisland, A., Pal, K., and Hewer, A. MetabolicActivation of Benzo[a]pyrene Proceeds by a Diol Intermediate. Nature,252:326-328,1974.
36. Stewart, R. F., Davidson,E. R., and Simpson, W. T. Coherentx-rayScattering for the Hydrogen Atom in the Hydrogen Molecule. J. Chem.Phys., 42: 3175-3187, 1965.
37. Sutor, D. J. The C—H. . . 0 Hydrogen Bond in Crystals. Nature, 195: 68-69,1962.
38. Swaisland,A. J., Grover, P. L., and Sims, P. Some Propertiesof “K-Region―Epoxides of Polycyclic Aromatic Hydrocarbons. Biochem.Pharmacol.,22:1547-1556,1973.
39. Wood,A.W.,Goode,R.L.,Chang,R.L.,Levin,W.,Conney,A.H.,Yagi,H., Dansette, P. M. , and Jenina, D. M. Mutagenic and Cytotoxic ActivityofBenzo[a]pyrene4,5-,7,8-,and9,10-OxidesandtheSixCorrespondingPhenols. Proc. NatI. Aced. Sci. U. S., 72: 3176-3180, 1975.
40. Yagi, H., Hernandez, 0., and Jenina, D. M. Synthesis of (±)-7@,8a-Dihydroxy-9@, 10@-epoxy-7,8,9,10-tetrahydrobenzo(a]pyrene, a Potential Metabolite of the Carcinogen Benzo[a]pyrene with StereochemistryRelatedto the AntileukemicTniptohides.J. Am. Chem.Soc., 97: 6881-6883, 1975.
atom of another molecule.Epoxidation increases the double-bond character of C-
11—C-i2, C-9-—C-10, and C-7—C-8.After the highly reactive oxide ring, the most reactive
positions are C-i and C-6, then C-7, C-i 1 , and C-12 asdetermined by a consideration of free valences, derivedfrom the experimentally determined bond lengths.
The oxide ring is more symmetrical (with C—O distances equivalent within experimental error) than is that ofthe K-region oxide of DMBA (where the difference in C—Odistances is 0.12 A). The external C—C-—Oangles in BP-4,S-oxide differ slightly, indicating a possible preference forcleavage of the C-5—Orather than the C-4—Obond, butthis preference is very small for BP-4,S-oxide (but morepronounced for DMBA-5,6-oxide). Thus the oxide rings ofthe K-region oxides of the 2 potent carcinogens, BP andDMBA, are not similar in dimensions.
ACKNOWLEDGMENTS
Wethank Dr. JensNyborgfor providingthe coordinatesof mezerein.
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