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Chapter 3
STRUCTURE-ACTIVITY RELATIOWSEIPS AMONG TEE CARCINOGENIC
AROMATIC AMIDES
In cer tain instances, aromatic amines are Conner ted in the host
organism to arylhydroxamic acids or arylhydroxylamine derivatives,
which are believed to be the ultimate carcinogenic fores of those
amine which are carcinogens (Miller and Miller, 1976~. m ese
substances induce tumors, usually in tissues distant from their
sites of administration (Clayson and Garner, 1976) . rhe tumor site
varies with the chemical, species, and strain of test animal used.
So far, there is little understanding as to why one aromatic
amine attacks one tissue while another amine affects a different
one. Irving (1979) discussed species and tissue differences in
aromatic amine metabolism as one factor in determining the
distribution of induced tumors. Other factors, such as differing
tissue and species levels in prereplicative DNA repair, cell
proliferation, and hormonal responsiveness, also need to be
considered before a comprehensive picture of tumor distribution can
be formulated. Besides the ~tructure-activity relationships of the
aromatic amines themselves, aromatic aroyl- and acylamides, aromatic
hydroxylamines and hydroxamic acids, and aromatic ado, hydrator
nitroso, and nitro compounds are also discussed in this chapter. In
this discussion, aromatic amines and their derivatives are regarded
as carcinogens if they significantly induce cancer in any tissue in
any species.
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Clayson (1953) suggested that, to be carcinogenic, an aromatic
amine had to:
o poseese two or three con fidgeted aromatic ring systems
{~.g., biptleny} or napbthalene) and
o have the amino group substituted in the aromatic ring
in the pare position to a conjugated aromatic system.
his suggestion has been refined more recently by the clear
demonstration that single-ring aromatic amines such as o-toludine
may induce cancer (We isburger et al ., 1978 I, although structures of
the type suggested by Clayson (1953) represent some of the more
potent carcinogens.
Another important discovery has been the demonstration of the
cons iderable carcinogen ic potency of certa in amino and
nitroheterocyclic aromatics, such as the derivatives of
S-nitrofuran, nitrothiazole, and nitroimidazole . mese compounds
also have considerable importance because of their use in medicines
for animals and bumans, to treat parasitic infections. Because
these substances; are structurally dissimilar to the simpler aromatic
amines, they are discussed separately.
The information on which the conclusions in this chapter are
based has been reviewed by Miller and Miller (1976), Clayson and
Garner (1976), and Weiaburger et al. (1978~.
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SUBSTITUENTS ON THE NITROGEN
Alkyla t ion
Alkylation of the aromatic amino group has been intensively
studied only with derivatives of p-dimethylaminoszobenzene. In this
particular series, the presence of at least one methyl group on the
amino group is held to be essential to hepatocarcinogenicity in
rats ; longer alkyl groups depress activity. Detailed examination
of the evidence supporting this statement reveals that few
nonalkylated derivatives (analogs of p-aminoszobenzene) beve been
studied and that the evidence for the essential nature of the methyl
group is confined mainly to 4-dimethylaminoszobenzene itself. In
specific cases, such as 3-methoxy-4-aminoazobenzene or
4-(o-tolylazo)~-toluidine, the N-methyl group is not essential, and
tumors are induced. Painting ~-aminoszobenzene or a range of
similar chemicals on rat skin leads to skin tumors (Fare and Orr,
1965; Fare, 19661.
There is very limited evidence for the importance of an alkyl
group on the nitrogen to the carcinogenic potency of aromatic
amines. A methyl group may be essential to the activity of
4-dimethylaminoazobenzene and certain of its analogs in rat
hepatocarcinoqenesis. Dimethyl derivatives are metabolically
monodemethylated to monomethylaminoszobenzene derivatives and then
to the unsubstituted amines. Contrary to earlier evidence, the
reverse process, arylamine methylation, is not a major metabolic
62
OCR for page 63
pa thway (Scr ibner et al ., 1965 ) . Bigher alkyl groups generally
result in chemicals with lower carcinogenicity than do those
provided by the free amines. Honoalkylaromatic dines can be
converted to the corresponding n$trosaeines in the presence of
nitrous acid at an acid pE.
Arylation
Ablation of the amino group to diarylamines or triarylamines is
believed to abolish carcinogenic activity, although the evidence for
this conclusion is tenuous. Phenyl-2-naphthylamine has been studied
intensively because of its use as a substitute for 2-naphthylamine,
a rubber-compounding ingredient. me urine of humans and dog e
exposed to this apparently noncarcinogenic cbeeica1 contains low
levels of free 2-naphthylamine (Batten and pathway, 1977; Mummer and
Tordoir, 1975; ~ . At this time, there is no explanation for this
finding--whether the 2-nap~thylamine is liberated within the host or
is an artifact of urine collection, or whether there is ~ similar
degradation of other dierylamines. The biologic significance of
this observation can be judged from the fact that the mount of
ur inary 2-naphthylamine found after exposing bumans to 10 as of
pbenyl-2-naphthylamine is equivalent to that in the sake of 4-40
cigarette';. Hoff's~ann et al. t1969, found 1 ~.~g of 2-napt~thylamine in
the smoke of 40 cigarettes.
A`:ylation
Acetylation and deacetylation of aromatic amines are coon
63
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metabolic reactions in most species, except dogs, which lack the
ability to acetylate these chemicals. Consequently, aromatic Mines
and acetamide~ generally possess similar carcinogenic potencies.
Higher homologs of the acetyl group do not appear to have been
investigated. N-2-fluorenylformamide is less potent than the ace~cyl
der ivative (Miller et al., 1962} .
Aroyl Der ivatives
Aroyl derivatives bave been examined, particularly in the
2-fluorenylamine ser ies . Although N-2-fluorenylbenzamide is
inactive, the corresponding N-hydroxy-2-fluorenylbenzamide is
carcinogenic. This finding suggests that aroylation blocks
N-hydroxylation, the essential activation route for this
carcinogen . The benzenesulfonamide der ivatives of 2-fluorenylamine
are likewise inactive, but its N-hydroxy derivative is carcinogenic
(Gutmann et al., 1967) .
N-Hydroxylat ion
N-Hydroxylation of aromatic amines or of their amides is
generally regarded as the f irst step toward their metabolic
activation. If active, aromatic bydroxylamines or hydroxamic acids
are more potently carcinogenic than are the non-N-hydroxylated
chemical=; however, the demonstration of this increase in potency
may require careful selection of a system (Miller et al., 1964) . In
specif to instances, the N-hydroxylated compound demonstrates
activity, and the parent compound does not. 1-Napb~bylamine, for
64
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example, is not demonstrably carcinogenic if free from the potently
carcinogenic 2-isomers bowever, the corresponding H-hydroxy
derivative, is carcinogenic (Rado~ki et al., 1971} .
Esters of N-HYdroxY Der ivatives
Esters of N-Bydroxy derivatives of aromatic amines have been
regarded as the ultimate carcinogenic form of the aromatic abides.
Some of These derivatives are highly genotoxic, if they can be
delivered to the test system and the critical receptors before they
interact with other possible targets suab as thiole. The less polar
model esters (such as N~acetoxy-2-fluorenylacetemide) are thus more
readily shown to be carcinogenic than are the more polar derivatives
(such as the sulfate ester of N-bydroxy-2-fluorenylacetamide).
Different esters appear to vary in their ability to act as
leaving groups in the production of *e arylnitrenium ion. For
example, the O-glucuronic acid ester of N-hydroxy-2-fluor
enylacetamide does not appear as capable of producing the nitreniue
ion as do either the ace toxy or sulfate esters (Irving and Wiseean,
1971) .
Azo Compounds and Bydrazo Compounds
m eve compounds are reduced in the anaerobic portions of the
gastrointestinal tract, or by the tissue enzyme, azoreductese, to
compounds, each of which contains an amino group. Severe1 examples
of azo compounds, themselves carcinogenic and capable of reduction
65
/
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to carcinogenic aromatic amines have been reported. Bonser et al.
1954 and Weisburger et al. (1978) reported that 1-to-tolyllazo~
2-napbthol is carcinogenic and may be reduced to o-toluidine, which
is also carcinogenic. Me high carcinogenic potency of ~ series of
dyes (Direct Black 38, Direct Brown 95, and Direct Blue 6), which
are capable of reduction to benzidine, has been reported by the
National Cancer Institute (1978~.
Aroma t ic C-Ni trove Compounds
These compounds are of interest because of their easy conversion
to arylhydroxylamines . Certa in C-nitroso compounds are effective
nitrosating agents.
THE RING SYSTEM AND The POSITION OF THE AROMATIC AMINO GROUP
Ring-sub~tituted amino derivatives of most substances containing
one, two, three, and possibly four aromatic rings may be
carcinogenic. The placement of the amino group is the critical
factor . Thus, 2-naphthylamine, 2-acetamidofluorene, 2-anthramine,
and 2-phenanthrylacetamide are potent carcinogens; 1-naphthylamine,
3-acetamidofluorene, 9-anthramine, and 9-phenanthrylacetamide are
not. The presence of a large conjugated group pare to the amino
group appears to enhance carcinogenic activity but is not a
requirement for this property, as is clearly demonstrated by the
fact that single-r ing aromatic amines and der i~ratives of
methylenedianiline are carcinogenic (International Agency for
Research on Cancer, 1974a,b,c; Weiaburger et al., 1978} .
66
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The basic ring system for carcinogenic aromatic amines may be
entirely carbocyclic {2-naphthylamine, 4-biphenylamine}, any show
limited numbers of heteroatoms (3-aminodiphenylene oxide,
4-~ - uinoline-1-oxide), or may be highly beterocyclic {nitridazole,
metronidazole}. The heterocyclic chemicals are d~wuseed separately
later in this chapter.
Ring substituents on the carcinogenic potential of aromatic
amines are subd ivided into
Analogs of ~-dimethylaminoszobenzene
Aromatic amines with single amino groups
Analogs of the phenylenediamines
Analogs of benzidine.
This subdivision is necessary because the various types of
carcinogenic aromatic amines appear to be affected differently by
substituents.
Analogs of P-DimethYlaminoa20benzene
Analogs of p-dimethylaminoszobenzene have been extensively
studied for their induction of rat liver tumors. were are five
different positions available for manosubstitution. The effects of
the substituents on carcinogenic activity are presented in Tables
3-1, and 3-2.
.67
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Table 3-1
Effect of Substituents on the CarcinogenicaAct~ivity of
N,N-DimethYl-p-phenyl2aoaniline-
SubstitilPot
2 3 2' a'
4' 2,3' 2,4' 2,6' 3',4' 3''5' 2 "4'.
-
-CH3
-C2H5
-CF3
-F
-C1
-Br
-OH
-OCH3
-oC2Hs
- NO2
-NH2
-SO3H
-CO2H
+ + +
-
-
~ ~ +
+ ~
+ + +
+ ~
+ _
+
+ +
a From Clayson and Garner, 1976, with permission.
b Ear duct, skin, and intestinal tumors, but no hepatomas.
c Bladder papillomas; hepatomas possibly induced
68
.
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~s1
In
Icy
-
·
o
-
Q.
1
-
I=
· -
c]
en
1
-
D
1 11
o
·_
·_
en
o
·_
~ ~ .
._ ._
~1
69
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Aromatic Amines Containing Single Amino Groups
mere aromatic amines have a number of similarities that lead to
structure-activity relationships.
Methyl Substitution. Especially when ortho to the amino group,
.
methyl substitution appears to entrance activity, as is demonstrated
by comparing the carcinogenic potential of 2' ,3-dimethyl-4-
aminobiphenyl to 4-aminobiphenyl, or of 3-methyl-2-amino-
naphthylamine to 2-naphthylamine. me effect of methyl groups in
other positions in the 4-aminobiphenyl system was extensively
studied by Walpole and Williams (19587. Methyl groups in both ortho
positions, as with 2,6-dimethylaniline (2,6-xylidine), may be
deactivating (National Cancer Institute, in press).
My. Ortho substitution of a methoxyl group
has a varied effect. onus, 3-methoxy.-4-aminobiphenyl and
1-methoxy-2-fluorenylacetamide are just as, or even more, potent
than the parent carcinogen in rats, although
3-methoxy-2-fluorenylacetamide was found to be without activity.
Similar results were reported for the free amines. Other ~nethoxyl
substitutions also make the molecule more carcinogenic as, for
example, in the case of ~cresidine as compared.to aniline or
7-methoxy-2-fluorenylacetamide as compared to 2-fluorenylacetamide.
Halogen Substitution. This is best illustrated by using
floor ine substitut ion to block metabol ic detox if ication of aroma tic
amides. Fluorine enhances carcinogenicity, as illustrated by the
70
OCR for page 75
appear to possess certain specific structural characteristics, such
~8
o one, two, or three conjugated aromatic ring systems,
o an aromatic amino group substituted in the position
pare to the conjugated aromatic system, or
o groups such as methyl, aethoxyl, or fluorine
substituted in specific positions relative to the
amino group.
Aniline, as the simplest aromatic amine, might be considered the
reference chemical for structure~carcinogenic activity relationships
in this ser ies. However, although it has induced cancer in rats
(National Cancer Institute , 1978q ), but not in mice , it has shown
negative results in mutagenicity tests. If norharmc~n is present in
Salmonella tests the results are positive (Hagao et al., 1977) .
—
Emus, it may induce splenic hemang iosarcoma and other sarcomas by a
ecbanism different from Mat by which other aromatic aaines induce
the ir ef feats . Ear example, the methemoglobinemis induced by
aniline may stress the spleen, which removes deter is in red blood
cells from the circulation, thereby setting up tbe conditions for
splenic tumorigenesis. ~C~loroaniline induces similar cancers and,
likewise, induce'; high levels of methemoglobinemia (National Cancer
Institute, 1979d) .
Et~Cr e s id i ne ~ 2-me theory- 5 -me thyla n i l i ne ~ induced bladde r
carcinomas and olfactory neuroblastomas in rats and bladder
75
OCR for page 76
care inomas and hepa tocellular carcinomas in mice (National Cancer
Institute, 1979c) . ~Cresidine produced positive results in
microbial mutagenicity tests. There in no reason to doubt that
genotoxic factors play a role in inducing these tumors and, as they
occur at sites usual for aromatic amines, ~cresidine should be
regarded as a potent carcinogen. The ortho methoxyl group is
probably responsible for enhancing the activity of thin amine.
2,4-Diaminotoluene (National Cancer Institute, 1978h) induced
hepatocellular carcinomas in male and female rats and in female
mice. In female rats, mammary adenocarcinomas were induced. The
substance is mutagenic in microbial systems. It is a genotoxic
carcinogen, and its activity is enhanced by the methyl group ortho
to the amino group.
Methylene-bisto-chloraniline' is clearly more carcinogenic than
is methylenedianiline (Munn, 1967) . It provides an example of the
enhancing effects of ortho chloro substitution; ortho methyl
substitution also enhances carcinogenicity.
Furazolidine is a borderline carcinogen. This is to be expected
from its single-ring structure, as activity in the nitro
heterocyclic series is highest when two aromatic heterocyclic ring
systems exist in the molecule .
76
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83
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85
Representative terms from entire chapter:
cancer institute
