[CANCER RESEARCH 36, 3951-3957, November 1976]
Molecular Structure of Benzo(a)pyrene 4,5-Oxide1
Jenny
P.Glusker,
David
E.Zacharias,
H.L.Carrell,
Peter
P.Fu,
and
Ronald
G.Harvey
TheInstitute for CancerResearch,TheFoxChaseCancerCenter,Philadelphia,Pennsylvania19111(J. P. G., 0. E. Z., H. L. C.),and BenMayLaboratoryfor
Cancer Research, The University of Chicago, Chicago, Illinois 60637 (P. P. F., R. G. H.J
SUMMARY
An X-ray crystallographic study of benzo(a)pyrene 4,5oxide, a metabohite of the carcinogen benzo(a)pyrene (BP),
has given information on the geometry of this molecule. The
carbon skeleton of BP itself has been shown by others to be
nearly planar; the plananity of the carbon skeleton has
been shown by this work to be perturbed very little by
epoxidation of the 4,5-double bond. Epoxidation has, how
ever, 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 points
directly toward the oxygen atom of another molecule. This
C—H . . . 0 interaction,
although
weak, suggests
that C-3
might be slightly acidic. An analysis of the experimentally
determined bond lengths indicates that, after the highly
reactive 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 ex
penimental error). The C—Cdistances are longer than those
found in most oxides, including those in 7,12-dimethyl
benz(a)anthracene-5,6-oxide. Thus it has been shown that
the oxide rings of the K-region oxides of the two potent
carcinogens BP and 7,12-dimethylbenz(a)anthracene
are
not similar in dimensions.
INTRODUCTION
Anene oxides have been postulated as the metabolically
activated forms of carcinogenic hydrocarbons (6), and evi
dence has been presented to support this theory. Thus the
K-region2 arene oxides have been shown to be more active
than the parent hydrocarbons in the transformation of
mammalian cells in culture (15, 17, 26), to be more highly
mutagenic (1) than either the parent hydrocarbons (16) on
the non-K-region oxides (38), and to bind covalently to
nucleic acids and proteinsin vivo (2, 5, 12, 25). On the other
hand, the tumonigenicity of these derivatives has been
shown to be lower than that of the parent hydrocarbons
(34), possibly
as a consequence
of ready conversion
highly reactive forms and to detoxification
1 This
research
was
supported
by
USPHS
Grants
K-region
in
a
polycyclic
ring
system
is
defined
CA-10925,
as
1976
interest
due to the ubiquitous
presence
MATERIALS AND METHODS
The compound to be studied, BP-4,5-oxide, was prepared
as described by Goh and Harvey (11). Crystals were grown,
and a structural analysis was then done by X-ray crystallo
graphic techniques. Details of the procedure are described
below.
Crystal Data. BP-4,5-oxide, C2OHI2O,monochinic space
groupP2,/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@ =
1.41 g-cm3, Dm 1.40 g@cm3.
Data Collection. Three-dimensional X-ray diffraction data
were obtained with CuKa-monochnomated radiation with an
automated 4-circle diffractometer. The 0-20 variable scan
technique was used to a maximum value of sin 0/A of 0.606
A-i . Of 2412 independent reflections measured, 1333 were
above the observational threshold of 2o-(/), where o-(I) was
derived from counting statistics. Values of o-(F) were deter
mined from the equation
to
CA-06927,
CA
a bond,
such
as
the
9,10-bond of phenanthrene, which undergoes addition reactions in the same
way that olefins do.
Received April 27, 1976; accepted July 22, 1976.
NOVEMBER
BP are of particular
of this carcinogen in the human environment (7). BP-4,5oxide has been detected as a metabohite of BP (13, 33) and
has been reported to be highly mutagenic in Salmonella
typhimurium and in Chinese hamster V79 cells (39).
o-(F)
(F/2){[i@(l)/P]
+ 62}J12
through enzy
11968, and RR-05539 from the NIH; BC-132 from the American Cancer
Society; AG-370 from the National Science Foundation; and an appropriation
from the Commonwealth of Pennsylvania.
2 The
matic reaction with glutathione on other cellular nucleo
philes.
Although considerable effort has been expended on in
vestigating the properties of hydrocarbon metabohites, the
nature of their chemical reactions leading to carcinogenesis
is largely unknown. Since more precise structural informa
tion may be expected to contribute to the elucidation of the
mechanism of induction of cancer by certain polycyclic
aromatic hydrocarbons, we have undertaken investigations
of the structures of selected metabolites of such cancino
gens by means of X-ray crystallographic analyses. We ne
port here the crystallographic study of the structure of the
K-region oxide of BP3, BP-4,5-oxide. The arene oxides of
where 8 is an instrumental uncertainty (6 = 0.020) deter
mined from the variation in measured intensities for some
periodically 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; DMBA
5,6-oxide, dimethylbenz(a)anthracene 5,6-oxide. R value = 1(1F01
—IF@II/1IF0I
where F0 is an observed structure factor and F@is a calculated structure
factor.
3951
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J. P. Glusker et a!.
was 0.1 x 0.1 x 0.4 mm. The density of the crystals was
measured in a mixture of carbon tetrachlonide and methyl
ene dichlonide. No correction for absorption was applied,
and the intensity fall-off, shown by measurements of stand
and reflections, was negligible as a function of time. Lorentz
and polarization corrections were applied to the intensities
to obtain values for structure amplitudes.
Structure Refinement. The structure was solved from the
Patterson map. Isotropic, then anisotropic, full-matrix least
squares methods were used to refine the structure. All
hydrogen atoms were located from a difference map calcu
hated at the stage at which all heavier atoms had been
refined anisotropically to convergence (R = 0.114). The
peaks selected from this map lay in the range 1.07 to 1.24
e/[email protected] hydrogen atoms were then refined isotnopically,
together with heavier atoms (which were refined aniso
tropically). The final residual is R = 0.065, and the weighted
residual is 0.069. The final difference map was featureless
and 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
programs
written in the Institute for Cancer Research laboratory. The
quantity minimized in the least-squares calculation was
@w{IIF0I—IF@II}2.
The weights of the reflections, w, during the
refinement were 1/[o-9F)J with zero weight for those neflec
tions below the threshold value. The atomic scattering fac
tons used for oxygen and carbon atoms (21) and for hydno
gen atoms (36) are listed in the literature.
Positional parameters are listed in Table 1. A list of ob
served and calculated structure factors is available from the
Editorial Office or the authors on request.
@
RESULTS
The carbon skeleton of BP-4,5-oxide is approximately
planar with the oxide ring inclined at an angle of 103°to it
(Chart ia). Some views of the molecule are shown in Chart 1
These and other changes are illustrated in Chart 2. In both
BP and BP-4,5-oxide,
the ring systems
are fairly flat (exclud
ing the oxide). The maximum deviation from the least
squares plane through the molecule of BP is 0.04 A for C-2
and C-i 1. In the case of the oxide, BP-4,5-oxide, the
deviation is slightly larger, i.e., 0.11 A for C-2. Thus epoxi
dation has had little effect on the general conformation of
the carbon ring system.
The interatomic distances and angles of the molecule
are shown in Chart 3. The oxide ring is distinguished by
much longer C—Obonds (1 .478 and 1.481 A) than those in
either the DMBA or phenanthrene K-oxides (1 .445 and
1.457, and 1.461 and 1.459 A, respectively) (9). Moreover,
although the C—Obonds are almost identical, the oxide
ring is not entirely symmetrical , since the external C—C—O
angles are 116.3°for C-i5—C-4—Oand ii4.9° for C-17—C5—O.The values of such angles for the symmetrical phen
anthrene 9,10-oxide are 115.5°,whereas for DMBA-5,6-ox
ide the analogous values are 117.9°and 114.3°.The unsub
stituted K-region bond between C-i i and C-i 2 is 1.338 A
long, nearly a pure double bond. Other short bonds are C9—C-b and C-7—C-8 with bond distances of 1.345 and
1.352 A, respectively.
Free valences (31) may be calculated from experimental
bond lengths. This is done (10) by summing the ir bond
orders around each atom and noting the difference from
that predicted theoretically. These free valences or unsatu
ration indices give an approximate measure of the suscepti
bihity of any atom to attack. Such studies of experimental
bond orders indicate that, after the highly reactive oxide
ring, 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 is
only 4.1 A long, is shown in Chart 4. The surroundings of an
isolated molecule are shown in Chart 5. Inspection of the
latter reveals that the ring bearing the oxide function (Ring
C―) lies under
the ring with the 2nd K-region
(Ring
E). The
separation between the planes through the aromatic ring
systems is 3.56 A, and the oxygen atom is directed away
(a to c). The maximumangulardeviationbetweenthe from the overlapping carbon ring system. For example, in
planes through each 6-membened ring is 5.14°(Table 2). Chart 5, the oxygen atoms (in Rings F and F―)lie below the
plane of the rest of the molecules when viewed from above
The root mean square deviation of all carbon atoms from
the plane of the paper. If the reverse were true and the
the least-squares plane through the ring system (excluding
the oxygen atom) is 0.05 A. The maximum deviations are oxygen atoms lay above the plane, an unreasonably close
0.1 1 A for C-12, 0.09 A for C-3, and —0.06A for C-li and C- approach to the next molecule would result, e.g., the oxy
gen atom on Ring F―would lie too close to Ring C.
16. The approximate plananity of the carbon skeleton
The environment of the oxygen atom of 1 molecule may
closely resembles the planar ring system of phenanthrene
9,10-oxide. This contrasts with the twisted geometry of provide clues as to any change distribution in the rest of the
molecule. It is found that there are 3 close approaches
DMBA-5,6-oxide (9).
The structure of BP was previously determined by Iball et between the oxide oxygen atom and the ring systems of
al. (19, 20) using crystallographic techniques. The major other molecules. These are listed in Table 3 and are illus
trated in Chart 5 by broken lines. Some interaction between
differences resulting from epoxidation of BP are a shorten
ing of the localized double bonds C-11——C-12,
C-9—C-10, the slightly negatively charged oxygen atom of 1 molecule
and C-7—C-8 to 1.338, 1.345, and 1.352 A (from 1.352, and C-4 and C-S of another molecule might be expected
properties of the oxygen
1.364, and 1.374 A), and a lengthening of the bonds C-S—C- from the electron-withdrawing
atom, which would affect these 2 carbon atoms more than
17, C-4—C-15, and C-4—C-5that lie near the oxide ring.
any others. This effect would be anticipated to aid the
stacking of molecules. This is the situation that is found in
this study. The additional interaction of the oxygen atom
Least Squares Program. UCLALS4 Program in Fortran IV.
with C(3―)
is of interest because the C—H. . . 0 interaction
4 P.
3952
K.
Gantzel,
R.
A.
Sparks,
A.
E.
Long,
and
K.
N.
Trueblood.
Full
Matrix
CANCER
RESEARCH
VOL. 36
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K-Region Oxide of BP
Table1
Refined atomic parameters
Positional parametersare listed as fractions of cell edges. Anisotropic temperature factors are expressedas
exp[_h/4(h2a*IB,,+ k2b*@B22
+ (‘C°2B,,
+ 2hka*b*B12+ 2hta°c°B,,
+
@@*c*B23)]
and isotropic temperature factors are expressedas
exp(—B sin2 0/A2)
with B values given
inxyin A2
parenthesesfor the last d.igits listed for any parameter.ained
Estimated
standard
B230
deviations,
z
C-i
C-2
0.1678(1)
0.0627(2)
0.1317(2)
(7) 0.3351(1)
0.3804(10) 0.0732(2)
0.5388(11) 0.0737(2)
C-3
0.1608(2)
C-4
0.1505(2)
0.1025(2)
C-5
from the least-squaresmefinement,are given
obt
82B,
B1B22B,.,
(2)
6.7 (2)
7.1 (3)
(2)
4.4 (2)
6.2(2)
0.6815(10) 0.1394(2) 5.1(2)
6.1(2)
6.8(2)
0.8122(9)
4.6(2)
6.1 (2)
0.2728(2)
6.2 (1)
7.5 (2)
6.4(2)
6.1 (2)
0.1 (1)
1.5 (2)
1.1 (2)
0.6(2)
—0.1
(2)
(1)
—0.7
(2)
0.3(2)
0.1 (1)
—0.7
(2)
0.5(2)
0.0(2)
1.1(2)
—1.1
(2)
0.3(2)
0.8153(9) 0.3411(2) 4.9(2)
4.4(2)
6.6(2)
(2)
0.4(2) —1.1
C-6
—0.0193
(2)
0.6764(9)
4.4 (2)
5.1 (2)
0.8 (2)
C-7
—0.1399
(2)
0.5388(9) 0.4641(2) 6.5(2)
C-8
C-9
C-b
—0.2106
(3)
0.4004(11) 0.4641(2)
—0.2392(2) 0.2504(11) 0.3997(3)
—0.1970
(2)
0.2394(10) 0.3372(2)
C-il
—0.1001
(2)
0.2160(9) 0.2001(2) 5.1(2)
5.1(2)
5.5(2)
C-12
—0.0575
(2)
0.2178(10) 0.1382(2)
5.9 (2)
5.2 (2)
0.0 (2)
4.7(2)
5.1(2)
5.8(2)
1.0(2) —0.3(2)—0.5(2)
(1)
0.1(2)
0.7(2) —0.7
0.6(2) —0.2(2) 0.0(2)
4.4(2)
4.9 (2)
0.3(2)
0.4 (2)
C-13
C-14
C-15
0.0176(2)
0.0456(2)
0.1193(2)
0.3989(2)
6.0 (2)
6.8 (2)
5.3(2)
5.6 (2)
6.4 (2)
—0.0018(2) 0.5073(8)
0.0258(2)
0.6636(9)
C-l8
C-19
C-20
—0.0746
(2) 0.3661(9) 0.2686(2) 4.9(2)
—0.1231
(2) 0.3772(9) 0.3341(2) 4.7(2)
—0.0943(2)0.5843
0.5329 (9) 0.3994 (2)
5.2 (2)
0.2708(2)
0.3384(2)
4.8(2)
5.0 (2)
x
1.0(2)
1.0 (2)
0.1 (2)
0.4 (2)
3.5(2)
3.8 (2)
0.159(3)
0.328 (9)
—0.7(2)
—0.3
(2)
0.1(2)
—0.2
(2)
1.2 (2)
0.2(2)
—0.9
(2)
0.6 (2)
0.9(2)
0.4 (2)
—0.1
(2) —1.2(2)—0.5(2)
—1
.3 (2)
—1
.4 (2)
—0.6(1) —0.4(1)
—0.6
(2) —0.2
(2)
(2)
0.3(2) —0.7
(2)
0.7(2) —0.5
0.9 (2) —0.4(2)
3.7(2) 5.1(2)
4.0(2) 5.1(2)
3.9 (2)7.2 5.0 (2)
y6.8
(2)
H-2
5.8(2)
6.3 (2)
7.4(2)
5.3 (2)
0.3659(10)0.1379(2) 5.5(2) 5.3(2)
0.5118(8) 0.2054(2) 4.7(2) 4.3(2)
0.6677(10)0.2045(2) 5.0(2) 4.8(2)
C-16
C-i7
BH-i
5.2(2)
6.9 (3)
6.8(2)
5.3 (2)
—1
.1 (2)
0.0(2)
0.5(2)
0.1 (2)
z—1.5
(2)
0.544(12)
0.024(2)
0.141 (2)
0.258 (2)
(1)
11 (2)
H-3
H-4
H-5
H-6
H-7
H-8
0.209 (2)
0.191 (2)
0.121 (1)
0.001 (2)
—0.118 (3)
—0.242 (2)
0.819
0.990
1 .005
0.809
0.700
0.371
H-9
—0.282
(2)
0.188(10)
0.403(2)
7 (1)
H-b
H-li
H-120.040
—0.214 (2)
—0.149 (2)
—0.078(2)
0.147 (8)
0.109 (10)
0.142(11)0.029
0.292 (2)
0.201 (2)
0.100(2)7
5 (1)
9 (1)
9(1)
is nearly linear (see Table 3), i.e., the hydrogen atom on C3―points directly toward the oxygen atom of the oxide
ring. The distances (Table 3) are near those of van den Waals
contacts (C . . . 0 = 3.1 A; H . . . 0 = 2.4 to 2.6 A) so that the
interaction is weak and longer than distances listed for
C—H . . . 0 hydrogen
bonds (37). However,
this situation
implies that there is a slightly acidic hydrogen atom on C-3,
which, in turn, implies that there may be some residual
positive charge on C-3.
DISCUSSION
Three-dimensional structure determinations of the K-ne
gion oxides of BP, DMBA, and phenanthmene reveal that the
hydrocarbon ring systems of both BP-4,5-oxide and phen
anthnene 9,10-oxide are essentially planar, whereas that of
DMBA-S,6-oxide is nonplanar with an angle of 35°between
the outer rings. The nonplananity of both DMBA and its 5,6NOVEMBER 1976
(9)
(9)
(6)
(10)
(ii)
(ii)
0.385 (1)
0.445 (2)
0.502 (2)
0.506 (2)
7 (1)
7 (1)
2 (1)
9 (1)
ii (2)
9 (1)
oxide (9, 10, 18) has been shown to be primarily a conse
quence of stenic repulsion between the 12-methyl group and
a hydrogen atom of the [a] ring. Thus the hydrocarbon ring
systems of K-region oxides of polycychic hydrocarbons
which lack such special stenic features would , in general , be
expected to be planar. It appears likely, however, in view of
the nonplananity of the hydrocarbon ring system of DMBA
and its known derivatives (9) and the planarity of the hydno
carbon ring system of BP, that plananity is not an important
factor in the cancinogenicity of polycyclic aromatic hydno
carbons (10).
The external angles about the oxide rings of the 2 carcin
ogen derivatives have been found to be less symmetrical
than those of phenanthrene oxide. This supports our previ
ously stated postulate (9) that the K-region oxides of carcin
ogens differ from their inactive counterparts by a polaniza
tion of the oxide functions, thereby leading to their en
hanced reactivity with cellular nucleophiles. This is in
agreement with the hypothesis of Miller and Miller (28) that
3953
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J. P. Gluskeretal.
I
la
lb
ic
Chart 1. Some views of the molecular structure of BP-4,5-oxide. •,oxy
gen atoms. a, view along the plane of the carbon skeleton; b, view onto the
plane of the carbon skeleton; c, general view of the molecule.
Table2
Planarity of the ring system
H
F
the active forms of most carcinogens are electnophiles
which initiate tumor formation through covalent interaction
with either nucleic acids on other cellular macmomolecular
targets. However, the amount of asymmetry in BP-4,5-oxide
is very much less than that found for DMBA-5,6-oxide. It is
found that DMBA-5,6-oxide reacts preferentially with gua
nine residues in nucleic acids to afford equal amounts of
the guanine-hydrocarbon adducts. These anise from neac
tion at both oxide ring carbon atoms (5, 22, 23). In contrast
to these results, reactions of DMBA-5,6-oxide with simple
nucleophiles (3) on acid-catalyzed solvolysis (14, 24, 29)
proceed via preferential opening of the C-6—Obond. In a
similar reaction with model nucleophiles (3), BP-4,5-oxide
furnished, unlike DMBA-S,6-oxide, essentially equal quanti
ties of the products of reaction at the 4- and 5-positions. The
reactions with simple nucleophiles were conducted under
conditions favoring an SN2mechanism of ring opening, i.e.,
high pH and a potent nucleophile, whereas the reactions
with nucleic acids were carried out near neutral pH, and
reaction occurred principally on the 2-amino group of gua
nosine, a relatively weak nucleophihic center. These results
suggest a greaten likelihood of an SN, process in this case.
Thus any effect that might favor enhanced SN, reactivity
may be important in the interaction of these compounds
with nucleic acids. It is, however, premature to draw any
firm conclusion regarding the relationship between struc
tune and biological activity of the K-oxides. Further struc
tunal investigations will be required to determine whether
asymmetry of the oxide ring is indeed a characteristic of the
oxides derived from carcinogenic hydrocarbons.
Since both BP and DMBA are carcinogenic, a comparison
of the K-region oxides of the 2 compounds was made in
order to determine the region of greatest similarity. Such a
.
region isfound inthe outer ringportionof region C-6 to C10 in BP-4,5-oxide, as judged from a comparison of bond
lengths. A similar comparison for BP and DMBA shows
Angles between p1anesin the
moleculeA: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.
similarities across the K-region (C-iS to C-i7) and in the
outer ring (C-7 to C-i9). The outer ring is the site of hydnox
ylation and epoxidation to give a 7,8-dihydro-7,8-dihydroxy
benzo(a)pynene-9,1 0-oxide (35), a postulated intermediate
in the carcinogenic process by BP. Our comparison of BP
and BP-4,5-oxide indicates that any puckering in the outer
ring (positions 7 to 10) of the diol epoxide will be caused
mainly by the saturation (on diol formation) at the 7- and 8Root-mean-square
deviations of carbon atoms from the least
A)A.0.0030
squares planes through each ring (in
positions and not by epoxidation at the 9- and 10-positions.
An analysis of the X-ray structural studies on epoxides
0.0072B.0.0037
E.
0.0000C.0.0i57
F.
revealed that several had been studied in great detail, in
0.0478D.0.0082
All rings
cluding 3 antileukemic agents, mezerein (30), tniptolide (8),
and tnipdiohide (8). In addition, good data are available on
+1.2
—
[email protected]@+l.4_l.2
@
—
‘ô
2a
3954
@6BP.
Chart 2. An indication of ma
jor differences between the
structure of BP and BP-4,5-ox
ide. Values given are those for
BP-4,5-oxide minus those for
a, bond distances showing
differences greater than 0.013 A;
b, interbond angles showing dif
ferences greater than 0.9°.
2b
CANCER RESEARCH VOL. 36
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K-Region Oxide of BP
o.@
in
124
1.478
1.02
1.04
1.15
LC15C4'O 116.3
LC17.C5-0114.9
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 those
involving 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 and
oxygen atoms and 2-3°if hydrogen atoms are involved.
C—
a
Chart 5.
gen atoms
translation
Portions of
@
The surroundings of 1 molecule (black bonds and atoms). Oxy
are stippled. A complete view of 2 molecules separated by a
is shown, and the overlap of rings is indicated by shading.
2 other molecules (see Table 3) are also shown.
bonds were 1.44 A, Ring C—Cbonds were 1.47 A, and the
average external 0—C—Cangle was 115.7°.The longer
C—O bonds in BP-4,5-oxide
1
@
@
Chart 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 is
formed.
tetracyanoethylene oxide (27) (including a neutron diffrac
tion study for comparison) and a diepoxycyclohexane (32).
In these and in the K-region oxides, the average Ring C—O
(1 .48 A) may imply a greater
ease of C—Obond breaking. The antileukemic agents have,
in some cases, hydroxyl groups on carbon atoms adjacent
to the epoxide rings. The conformations axia cis (trip
tolide, tripdiohide, with 0 . . . 0 distances of 2.75 to 2.78 A),
equatorial cis (diepoxycyclohexane, 0 . . . 0 = 3.01 A), and
equatorial trans (tniptohide, tnipdiohide, mezerein 0 . . . 0 =
3.64 to 3.68 A) are illustrated
in Chart 6. In the case of trip
diohide, the hydroxyl group forms a hydrogen bond to an
NOVEMBER 1976
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1976 American Association for Cancer Research.
3955
@
0@
J. P. Glusker et a!.
epoxide oxygen atom in another molecule. No intramolecu
lar hydrogen bond is formed. However, the 14f3-hydnoxyl
group (0-4) is only 3.13 to 3.15 A from the epoxide oxygen
to the diol epoxide,
suggested
as the active
metabolic
inter
mediate in carcinogenesis by BP (35), has been pointed out
(40).
In summary, this structural study has yielded the follow
atom (0-6)(32).The relationship
of tniptohide
and tripdiolide
ing informationon BP-4,5-oxide,a metabohiteof the cancin
Table3
ogen
Close approaches to the oxygen atom in the crystalline state
O...C(A)
C-3―,H-3―
2.42169°C-4'―,
3.42
2.82112C-5―
H-4'°
2.66117Estimated
, H-5―
3.36
3.35
O...H(A)
O...H—C
2-3°Code:
S.D. values 0.04-0.05 A and
5)II.
I. @/2 X, @/2
+ y, @/2
—z (Chant
5)III.@/2 X, y —@/2,@/2 Z (also Chart
x, y —1, z
@
@L_@
1.49#@
@
114.9
4,5-oxide.
The atom C-3 of BP-4,S-oxide may be slightly acidic, since
a linear
15
5
BP.
The C—Obond lengths of BP-4,5-oxide are longer than
those 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 is
fairly planar. The work reported here shows that the planar
ity of the carbon skeleton of BP has been perturbed very
little by epoxidation of the 4,5-double bond to give BP
C—H . . . 0 interaction
is formed
with
the oxygen
16
,@,_o
116@3is
115.51.481.481.451.461.461.461i@g
5
6
1.50
114.3115.415
10
9
116.3
(a)
(b)
149
116.1
1.42
X-ray d,ftr@t,n,,
Cc)
1163
1.43
neutron diffr@tion
Cd)
(d)
axial
trans
115.1
1
ec@iator@
trans
7
1.44
@5
145
17
ec@iator'al
trans
e@@jator@al
C's
6
(e)
2
\
Ce)
@1A62/@
145
[email protected]
3
146
8
L 1.50@###@4
14
13
12
114)@@
5
(1)
1.46\@/@
\444@;,
°‘¼@@7'@
Cg)
Cg)
8
@
13
°‘@14
@
4
tr5115
12 145
12
147
10 @‘@—_@—‘@
115.9r$@
11/ 1152
i@
@
(g)
17
0
@
13@@
1.45\.y/4'1i:@'
6
Ch)
1J45\S%J@;'
(h)
axtai
1
Ch)
17
,0
..@
111213
6
..@
16
‘H
@
(,)
(k)
Chart 6. Dimensions of the epoxide ring in some compounds studied crystallographically. a, BP-4,5-oxide (this work); b, DMBA-5,6-oxide (9); c,
phenanthrene 9,10-oxide (9); d, tetracyanoethylene oxide (27); e, diepoxycyclohexane (32); f, mezerein (30); g, triptolide (8); h, tripdiolide (8). Formulae of i,
triptolide (A = H) (9), tripdiolide (A = OH) (h); j. mezerein (1) (R' = —‘CO-—CH==CH--—C@H5);
k. diepoxycyclohexane (e).
3956
CANCER RESEARCH VOL. 36
Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1976 American Association for Cancer Research.
K-Region Oxide of BP
atom of another
Epoxidation
14. Harvey,R.G.,Goh,S.H.,andCortez,C. “K-Region―OxidesandRelated
molecule.
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 as
determined
by a consideration
from the experimentally
of free valences, derived
determined
bond lengths.
The oxide ring is more symmetrical (with C—O dis
tances equivalent within experimental error) than is that of
the K-region oxide of DMBA (where the difference in C—O
distances is 0.12 A). The external C—C-—Oangles in BP-4,Soxide differ slightly, indicating a possible preference for
cleavage of the C-5—O rather than the C-4—Obond, but
this preference is very small for BP-4,S-oxide (but more
pronounced for DMBA-5,6-oxide).
Thus the oxide rings of
the K-region oxides of the 2 potent carcinogens,
BP and
DMBA, are not similar in dimensions.
ACKNOWLEDGMENTS
Wethank Dr. Jens Nyborgfor providing the coordinatesof mezerein.
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Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1976 American Association for Cancer Research.
3957
Molecular Structure of Benzo(a)pyrene 4,5-Oxide
Jenny P. Glusker, David E. Zacharias, H. L. Carrell, et al.
Cancer Res 1976;36:3951-3957.
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