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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. 60
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~. 61
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
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
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
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 /
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
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
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 .
~s1 In Icy - · o - Q. 1 - I= · - c] en 1 - D 1 11 o ·_ ·_ en o ·_ ~ ~ . ._ ._ ~1 69
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
potent carcinogens 4'-fluoro-4-biphenylamine and 7-fluoro-2-fluorenylacetamide. Most fluoro derivatives of N-2-fluorenylacetemide have been tested (Miller at al., 1962~. Ineoffictent cats are available to permit a useful statement on other balogen-substituted aromatic seines. Polar Group Substitution. It is generally held that substitution with sulfonic acid, carboxylic acid, or phenolic groups diminishes the carcinogenicity of aromatic amines. m ere are, however, few published animal studies to support this viewpoint. Epidemiology can do little to provide useful information because the noxious parent aromatic amines are usually used in proximity to the polar derivatives. Analogs of Phenylenediamines More than 14 phenylenediamines or the corresponding nitro compounds have been adequately tested . for carcinogenicity (National Cancer Institute, 1978a,b,c,d,e,f; 1979a,b; Weisburger et al., 19781. A limited number of these agents are effective carcinogens, including 2, 4-diaminotoluene, 5-nitro~o-anisidine, and 4-chloro~o-phenylenediamine; others, under the test conditions used, exhibited more marginal carcinogenicity, including 2-N-~-phenylenediamine, 2,5-diaminotoluene sulfate, 2,4-dinitrotoluene, and tetrafluorometaphenylenediamine. me remainder were inactive. 71
This evidence demonstrates that derivatives of each of the three positional isomers of phenylenediamine or the corresponding nitro compounds may exhibit carcinogenicity. So far as the limited data permit a decision, it appears that the carcinogenicity of phenylenediamine, is activated by the presence of ~ methyl or methoxyl group ortho to one of the amino groups in the same way as are the aromatic monoamines. Blocking metabolically important positions for detoxification, as in tetrafluoro~etaphenylenediamine, may also be important. Analogs of Benz idine Information obtained mainly from studies of rats indicates that benzidine is more carcinogenic than o-tolidine, o-dianisidine, or o-dichlorobenzidine. In a limited study, 3,5,3',5'-tetramethyl- benzidine appears inactive. Overall, benzidine derivatives appear to behave differently in their structure-activity relationships than do either the aromatic monoamines or derivatives of methylenetb~-aniline), in which o-methyI- or o-chloro-substitution appears to enhance carcinogenicity (Munn, 1967~. NTTRO- AND AMTNO-AROMATIC ""R=YCLIC =~=DS In the furan, thiophene, imidazole, and thiazole series, both of the unsaturated bonds provide a pair of ~ electrons, and one of the betero atoms provides a lone pair of electrons to form the aromatic sextet. Thus , the amino and nitro derivatives of these heterocyclic resemble the carbocyclic analogs in various ways, including cancer 72
induction. The initial discovery by Price et al. {1966) and Stein at al. (1966) has been followed by the blosesay of asny environmentally important subetances of this type (Table 3-3). m. nitrofuran derivatives have been fully reviewed by Bryan {19781. It is apparent that many of Me nitroheterocyclic compounds are potent carcinogens wi tb demonstrable ef feats in Many tissues . The an~ino-subatituted analogs have been much less intensively studied. Structure-activity relationships are cliff icult to evaluate because of the competing effects of the betero atoms, the substitutents, and the various conjugated aromatic systems. It does, however, appear that compounds with two conjugated aromatic ring systems are, when carcinogenic, more potent than are single-ring systems. mug, the low activity of the ~ingle-ring substance, metronidazole {Flagyl~)), can be compared to the considerable carcinogenic potency of niridazole, which possesses two ring systems (Bulay et al., 1977 s Rustia and Shubik, 1972) . OONCLUS IONS - Many aromatic amino and nitro compound2; can induce cancer in humans or animals . Unless polar groups, such as sulfonic acid or carboxylic acid ';ubetituents, are present in the molecule, it is possible that these chemicals are potentially carcinogenic. fortunately, however, the most potent aromatic amine carcinogens 73
~l ~n c' - - c~e ~e ~n o . E C~ N_e ~e O ~, S- te _ 1 C~ o - ~e o ~e S - e tlli]~07~11 j~ll111~dll~lilll ~ , ~ 11+ + ++++ ,++, , , + , , ,+ + + + 4~1 1 611 1 11 1 i. 1 d) 3 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1_ 1 1 1 1 1 1 1 1 1 1 + ~re I + I I I I 1 1_ 1 1 I I I I I I I L 1 + 1 1~1 1 1 1 ++++ I I I I I I I I t I I I 0 ~.e 0 0 ~ 0 ~ ~.e 0 e 310 11e 11t ~ 1 1 i] oo ooooo ooo 0 0 o 1_ 1 1 1 1 1 1 1 1 I I I I l I I 1 1 1 +1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ~ t I 1 1 1 1 1 1 1 1 ++ _ 1 1 + +_ 1 1 1 1 ~ 1 1 t I 1 1 ~ I I ~ 81 Ill, eae I 1 1 1 1 1 1 1 1 ++ 1 1 1 ~ _ 1 1 1 1 1 1 ~ 1 1 1 1 1 1 1 1 1 1 eae I I I 1 I ~ 74
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
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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