Cancer Risk Reduction Through Mechanism ... - ACS Publications

Chapter 3

Cancer Risk Reduction Through MechanismBased Molecular Design of Chemicals 1

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Downloaded by NANYANG TECHNOLOGICAL UNIV on August 23, 2015 | http://pubs.acs.org Publication Date: May 5, 1996 | doi: 10.1021/bk-1996-0640.ch003

David Y.Lai ,Yin-takWoo ,Mary F. Argus , and Joseph C. Arcos 1

Office of Pollution Prevention and Toxics, U.S. Environmental Protection Agency, Mail Code 7406, 401 M Street, SW, Washington, DC 20460 School of Medicine, Tulane University, New Orleans, LA 70112

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Increased understanding of the mechanistic basis of chemical carcinogenesis and the relationship between molecular structure and carcinogenic activity provides opportunities not only for identifying suspect carcinogens but also for designing chemicals with lower carcinogenic potential. One of the chemical classes in which the structural and molecular basis of carcinogenicity is the most clearly understood is the aromatic amines. This paper summarizes the bioactivation mechanisms and structural criteria for aromatic amine carcinogenesis; a strategic approach of risk reduction through mechanism-based molecular design of aromatic amine dyes with lower carcinogenic potential is discussed. With our increasing knowledge of the mechanisms and structure-activity relationships, it should be possible to develop safer products for other chemical classes using similar molecular design approaches.

Mechanisms of Chemical Carcinogenesis and Structure-Activity Relationships Considerable knowledge of the mechanisms of chemical carcinogenesis has accrued since the pioneer work by James A. and Elizabeth C. Miller at the University of Wisconsin beginning in the 1940's, particularly concepts on the metabolic activation of chemicals to reactive electrophilic intermediates that interact with cellular nucleophiles to initiate carcinogenesis (7,2). For many carcinogen classes, the molecular basis of carcinogenic activity is now known in considerable detail and the concept of electrophiles provides the most probable rationale for their carcinogenic action. Some of the electrophilic, reactive intermediates believed to be responsible for the carcinogenicity of genotoxic chemicals include: carbonium, aziridium, episulfonium, oxonium, nitrenium or arylamidonium ions, free radicals, epoxides, lactones, aldehydes, semiquinones/quinoneimines, and acylating moieties. The metabolic activation of various genotoxic chemicals to their ultimate carcinogenic metabolites has been reviewed (3). 0097-6156/96/0640-0062$15.00/0 © 1996 American Chemical Society

In Designing Safer Chemicals; DeVito, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1996.


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Although a chemical may have the potential to produce electrophilic reactants, it is also known that its carcinogenic activity depends on a host of other factors. Several significant molecular parameters that may affect the carcinogenic potential of electrophiles include: (i) molecular size and shape, (ii) substituent effects (electronic or steric), (iii) molecular flexibility, and (iv) polyfunctionality and spacing/distance between reactive groups. For instance, the molecular size (as measured by incumbrance area of planar molecule) of most potent carcinogenic polycyclic aromatic hydrocarbons (PAHs) lies within a certain range. Virtually all PAHs with highly elongated shape tend to be inactive. Ring substitution with methyl group(s) at detoxification sites (e.g. L-region) tends to increase carcinogenic activity whereas ring substitution with bulky or hydrophilic substituents invariably decreases activitiy particularly near or at proelectrophilic regions such as the bay region (4-6). The importance of molecular flexibility can be illustrated by the findings that epoxides on rigid cycloaliphatic rings tend to be considerably less active than epoxides on more flexible noncyclic aliphatic chains. Diepoxides are invariably more carcinogenic than monoepoxides particularly if the two epoxy groups are favorably apart to impart crosslinking activity (7,8). The knowledge of molecular mechanisms and of other factors that affect carcinogenesis by various types of chemical carcinogens has established the basis for identifying suspect carcinogens by Structure-Activity Relationships (SAR) analysis, which has routinely and effectively been used by the U.S. Environmental Protection Agency (EPA) to evaluate Premanufacture Notification (PMN) chemicals regulated under Section 5 of the Toxic Substances Control Act (TSCA) (9). The state-of-the-art of predicting suspect carcinogens based on SAR analysis has previously been presented (7,8). Increased understanding of the mechanistic basis of chemical carcinogenesis and the relationship between molecular structure and carcinogenic activity provides opportunities not only for identifying suspect carcinogens but also for designing chemicals with lower carcinogenic potential. One of the chemical classes in which the structural and molecular basis of carcinogenicity is the most clearly understood is the aromatic amines. This paper summarizes the bioactivation mechanisms and structural criteria for aromatic amine carcinogenesis. A strategic approach of risk reduction through mechanism-based molecular design of aromatic amine dyes with lower carcinogenic potential is discussed. Aromatic Amine Dyes and Structural Criteria for Carcinogenicity Aromatic amine derived dyes are synthetic organic colorants of considerable industrial and commercial importance. They are widely used in textile, paper, leather, plastics, cosmetics, drug and food industries. Several aromatic amines, such as benzidine, 2-naphthylamine, 4-aminobiphenyl are known human carcinogens (10). The recognition that these and other aromatic amines are carcinogenic led to the abandonment of many of these compounds by the dye industry and prompted a search for safer replacement products. Since the 1950's, a considerable number of aromatic amines have been tested for carcinogenicity. Carcinogenicity data are available for many aromatic amines with diverse ring systems and different substituents, thus allowing SAR analysis and the determination of structural criteria for carcinogenic activity (11,12).



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DESIGNING SAFER CHEMICALS

The basic requirements for an aromatic amine to be carcinogenic are: the presence of an aromatic ring system (a singleringor more than one ring forming a conjugated system, fused or non-fused) and of the amine/amine-generating group(s). Figure 1 shows the aromaticringsystems in some well-known carcinogenic aromatic amines. The unattached bonds on these ring systems indicate the positions where attachment of amine or amine-generating group(s) gives rise to carcinogenic compounds. Owing to the possible metabolic interconversion of the amino group with hydroxylamino and nitroso groups and the metabolic reduction of the nitro to nitroso, the latter three groups (i.e. hydroxylamino, nitro and nitroso) are often termed "amine-generating groups". In some cases, replacement of an amino group with a dimethylamino group does not result in a significant loss of the carcinogenic activity of aromatic amine compounds since metabolic N-demethylation readily occurs in vivo. Therefore, some monoalkylamino/dialkylarnino groups are also aminegenerating groups. Beyond the presence of an aromatic ring system and of amine/aminegenerating group(s), SAR analysis has revealed several structural features important for predicting the carcinogenicity of aromatic amines. These include: (i) number and nature of aromaticrings;(ii) nature of amine/amine-generating group(s); (iii) position of anrine/amine-generating group(s); (iv) nature, number and position of other ring substituent(s); and (v) size, shape and planarity of the molecules (72). Interestingly, many of the structural features that are important for the carcinogenicity of aromatic amines also have important influences on their bioactivation mechanisms. Bioactivation Mechanisms in Relation to Structural Criteria for Carcinogenicity of Aromatic Amine Dyes The aromatic amines require a two-stage metabolic activation for carcinogenicity, and the mechanism of activation is now known in considerable detail (rev. 3,13,14). The first stage of metabolic activation involves N-hydroxylation and/or N-acetylation to yield the respective N-hydroxylated and/or N-acetylated derivatives. The second stage involves O-acylation (where the acyl group can be sulfonyl, phosphoryl, or acetyl) and N-, or O-glucuronidation in the formation of acyloxyamines and glucuronides. Many of the enzymes (e.g. acetyltransferase, sulfotransferase) involved in these reactions have been identified and recendy been characterized at the molecular level (15,16). The multiple metabolic activation pathways of aromatic amines are summarized in Figure 2. The acyloxyamines are highly reactive and, upon departure of the acyloxy anion, the arylamidonium/arylnitrenium ion formed may readily bind covalendy to cellular nucleophiles such as DNA to initiate carcinogenesis (13,17). The glucuronides, on the other hand, are essentially unreactive and represent stable excretion productsfromthe liver (the site of their formation). In rodents, glucuronide formation is actually a detoxification pathway. However, at the acidic pH found in the urinary bladder of dogs and humans, and in the presence of urinary 8glucuronidase, they are cleaved to give the electrophilic arylnitrenium ion which interacts with cellular macromolecules such as DNA to induce bladder tumors (18). There is also evidence that some aromatic amines may induce bladder tumors via the formation of a reactive quinoneimine metabolite after bioactivation by



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Figure 1. Aromatic Ring Systems in Some Carcinogenic Aromatic Amines. The unattached bonds on these ring systems indicate the positions where attachment of amine or amine generating group(s) gives rise to carcinogenic compounds. (Reproduced with permissionfromreference 8. Copyright 1978, Begell House, Inc.)




UH peroxidases

^- ' = > —,

acetyl CoA

OH

>

cyt.P-450s OH

+

NHAc

cyt.P-450s OH

I

I

NH

deacetylases, and/or H

.

NAe

trans\l-eIectron ^vsulfotransferases acetylases \ oxidation -f +PAPS dismutatlon

OAc

Jj %-so

ELECTROPHILIC METABOLITES

COVALENT BINDING TO DNA

i i i CANCER

jure 2. Multiple Metabolic Activation Pathways of Aromatic Amines.


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peroxidases, such as prostaglandin H synthase (PHS) which has been detected at high levels in dog bladder (19,20). Number and Nature of Aromatic Ring(s). The bioactivation mechanisms of aromatic amines have previously been discussed (4,9). The carcinogenic potency of aromatic amines is a function of the leaving potential of the acyloxy anion which is governed by the force of conjugation of the respective aryl moieties. The roles of the aromatic moiety are: (i) to providerc-electronshift of sufficient strength to facilitate the departure of the acyloxy anion; and (ii) to stabilize the electrophilic nitrenium ion. Therefore, an aromatic ring system is essential to the carcinogenicity of aromatic amines; many heterocyclic aromatic amines (e.g. amino-imidazoles, amino-carbolines formed during the cooking of food; 21) but not non-aromatic cyclic amines are also carcinogenic. The force of conjugation, facilitating the departure of the acyloxy anion, increases from phenyl toward higher aryl groups. This is consistent with the findings that aniline (single phenylring)is a weaker carcinogen than benzidine or Bnaphthylamine (two phenyl rings). Nature of Amine/Amine-generating Group(s). An amine/amine-generating group is required since the first stage of metabolic activation involves N-hydroxylation and/or N-acetylation of the amine/amine-generating group(s) to yield the respective N-hydroxylated and/or N-acetylated derivatives, and subsequendy the reactive eletrophilic nitrenium ion. The nature of the amine-generating groups is important, since for dialky amino groups with bulky or long alkyl substitution N-dealkylation does not readily occur to allow further bioactivation. Replacement of the dimethylamino (-NMe^ group of 4-dimethylaminoazobenzene by a diethylarnino (NEt^ or a higher dialkylamino group has been shown to lead to marked attenuation of its carcinogenicity (11) and mutagenicity (22). Position of Amine/Amine-generating Group(s). The position of the amine/ aminegenerating group(s) is important because it may affect the molecular shape/planarity of the molecules and the susceptibility of the group(s) being substrates for the oxidizing or acetylating enzymes (see discussions on "planarity of molecules" below). In addition, the force of conjugation which facilitates the departure of the acyloxy anion to form the ultimate carcinogenic metabolites, increases with the length of the conjugated double-bonded system involved. Within a given molecule, the force of conjugation is greatest when the amine/amine-generating group is linked to the aromatic frame in position(s) corresponding to the terminal end(s) of the longest conjugated system in the molecule (8). As shown in Figure 1, consistent with this bioactivation mechanism most potent carcinogenic aromatic amines have the amine/amine-generating group(s) linked to the aromatic frame in position(s) corresponding to the terminal end(s) of the longest conjugated system of the molecule (e.g. 2-position of 6-naphthylamine, 2-acetylaminofluorene and 2aminoanthracene; 4-position of 4-aminobiphenyl and 4-aminostilbene; as well as the amino groups in benzidine and 2,7-bisaminofluorene).




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Nature, Number and Position of Other Ring Substituent(s) - Substituents Effect. Substitution on the rings may exert electronic or steric effects on the reactivity and stability of the ultimate carcinogenic metabolite(s). There is evidence from SAR analysis on analogues of aniline, phenylenediamine and methylene-bis-aniline that substitution of a chloro group or a methyl/methoxy group ortho to the amino group often enhance reactivity (carcinogenicity and mutagenicity) (23-25). However, the effect of ortho substitution is related to the size of the alkyl groups; the larger the substituents, the less potent the mutagenic/carcinogenic activity. If both ortho positions of an amino group are substituted by large alkyl groups, an additional decrease in activity occurs; this is because large alkyl substituents at the ortho position provide steric hindrance around the amino group thus inhibiting hydroxylation/acetylation — the necessary steps required for metabolic activation to the ultimate mutagenic/ carcinogenic species. Arylamines are oxidized to form a number of ring hydroxylated products in addition to a N-hydroxylated metabolite. The ring hydroxylated products are generally considered products of detoxification. However, ring hydroxyl substituents ortholpara to amino groups can form quinoneimines which are reactive and can bind to cellular nucleophiles to initiate carcinogenesis. The formation of a reactive quinoneimine metabolite after bioactivation of benzidine and other aromatic amines by peroxidases such as prostaglandin H synthase (PHS) has been demonstrated (2026). Planarity of Molecules. SAR analysis has shown that the planarity of the molecule is an important determinant in the metabolic activation of aromatic amines. For instance, studies by Ioannides and coworkers (27) on the three isomeric forms of aminobiphenyl show good correlations among mutagenic/ carcinogenic activity, the capability of N-hydroxylation, and the planarity of the molecules. Both the 3- and 4- isomers are planar and can be N-hydroxylated; 3aminobiphenyl is a weak carcinogen, whereas 4-amino-biphenyl is a potent carcinogen. The presence of an amino group/substituent at the 2-position of aminobiphenyl results in marked loss of planarity; this is because 2aminobiphenyl, being nonplanar, does not form any N-hydroxylation products in vitro, and is noncarcinogenic and nonmutagenic. Isozymes of the cytochrome P450 families such as cytochrome P-450 1A2, which catalyse the N-hydroxylation of many aromatic amines including 4-aminobiphenyl cannot N-hydroxylate 2aminobiphenyl since these enzymes are unable to carryout oxygenation at conformationally hindered positions. The non-planarity of the compound, therefore, precludes it from being a substrate for the cytochrome P-450 oxidizing enzymes of N-hydroxylation. Similarly, the presence of substituent(s) ortho to the intercyclic linkage (at the 2- or 2'-position) of benzidine will result in marked loss of planarity and will render it a poor substrate of the cytochrome P-450 oxidizing enzymes for Nhydroxylation. Hence, the amino groups of /w-tolidine and of other 2-substituted or 2-,2'-disubstituted benzidines may not be readily activated metabolically. A recent National Toxicology Program carcinogenesis bioassay has shown that 4,4'diamino-2,2-stilbenedisulfonic acid was inactive in male and female rats and mice (28). This may be partly because of the sulfonation effect (see discussions ,


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below) and partly because of the substituent effect of the sulfonic acid group on the planarity of die molecule. In addition to affecting metabolic activation, planarity is also expected to affect the potential of aromatic amines to serve as intercalating agents.


Molecular Design of Aromatic Amine Dyes of Low Carcinogenic Potential With the understanding of the bioactivation mechanisms and the structural requirements for the carcinogenicity of aromatic amine dyes, safer dyes with low carcinogenic potential can be designed through modifications of their chemical structures by a number of approaches. These approaches along with their rationale are discussed below and are summarized in Table I. Introduce Bulky Substituent(s) ortho to the Amine/Amine-generating Group(s). Since the first stage of metabolic activation of aromatic amine dyes involves N-hydroxylation and/or N-acetylation to yield the respective Nhydroxylated and/or N-acetylated derivatives, introducing bulky substituent(s) ortho to the amine/amine-generating group(s) will provide steric hindrance to inhibit bioactivation by the oxidizing/acetylating enzymes. Introduce Long-chain Alkyl or Bulky N-substituent(s) to the Amino Group(s). Introducing long-chain alkyl or bulky N-substituent(s) to the amino group(s) will make the chemicals poor substrates for the oxidizing/acetylating enzymes. This is because prior to bioactivation, N-dealkylation is required and for (halkyamino groups with bulky or long alkyl substitution, N-dealkylation may not readily occur to allow further bioactivation. Introduce Bulky Groups ortho to the Intercyclic Linkage(s). For aromatic amine dyes with more than one, non-fused rings, introduction of bulky groups ortho to the intercyclic linkages (2,2'-positions) will distort the planarity of the molecule and render it less favorable for DNA intercalation and a poorer substrate for the bioactivation enzymes. Alter the Position of the Amine/Amine-generating Group(s). The carcinogenic potential of aromatic amine dyes can be reduced by altering the position of the amine/amine-generating group(s) on the aromatic ring(s) of carcinogenic aromatic amines (shown in Figure 1) because it will: (i) reduce the length of the conjugation path and thus the force of conjugation which facilitates the departure of die acyloxy anion; (ii) distort the planarity of the molecule making it less favorable for DNA intercalation and a poorer substrate for the bioactivation enzymes; and (iii) render the conjugation path non-linear and thus less resonance stabilization of the electrophilic nitrenium ion will occur. Resonance stabilization of reactive intermediates is important for carcinogenicity of chemicals since stabilized reactive intermediates have a better chance of remaining reactive during transport from the site of activation to target macromolecules; compounds which yield reactive intermediates that can be stabilized by resonance often have higher carcinogenic potential (9).


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Table I. Molecular Design of Aromatic Amine Dyes with Lower Carcinogenic Potential Approaches Rationale 1. Introduce bulky substituent(s) Provide steric hindrance to inhibit ortho to the amine/amine-generating bioactivation. group(s). Make the dye a poor substrate for 2. Introduce bulky N-substituent(s) to the amine/amine-generating group(s), the bioactivation enzymes. 3. Introduce bulky groups ortho to the intercyclic linkages.

Distort the planarity of the molecule making it less accessible and a poorer substrate for the bioactivation enzymes.

Alter the position of the amine/ aromatic ring(s).

A. Reduce the length of the conjugation path and thus the force of conjugation which facilitates departure of the acyloxy anion. B. Non-linear conjugation path; less resonance stabilization of the electrophilic nitrenium ion. C. In some cases, distort the planarity of the aminegenerating group(s) in the molecule making it less favorable for DNA intercalation and a poorer substrate for the bioactivation enzymes.

5. Replace electron-conducting intercyclic linkages by electroninsulating intercyclic linkages.

A. Disrupt the conjugation path and thus reduce the force of conjugation which facilitates the departure of the acyloxy anion. B. Less resonance stabilization of the electrophilic nitrenium ion.

6. Ring substitution with hydrophilic groups (e.g. sulfonic acid); especially at the ring(s) bearing the arnine/arnine-generating group(s)

Render the molecule more water soluble thus reducing absorption and accelerating excretion.


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Replace Electron-conducting Intercyclic Linkages by Electron-insulating Intercyclic Linkages. For aromatic amine dyes with more than one, non-fused rings, replacing electron-conducting intercyclic linkages (e.g. single bond, -CH -, CH=CH-) by electron-insulating intercyclic linkages [e.g. -CO-CH -, -(CH^- for n>l] will disrupt the conjugation path and thus the force of conjugation. Further, it will provide less resonance stabilization for the electrophilic nitrenium ion. 2


2

Introduce Hydrophilic Groups into the Ring(s). Ring substitution with hydrophilic groups (e.g. sulfonic acid, carboxylic acid), especially at the ring(s) bearing the amino/amine-generating group(s) will reduce their carcinogenic potential since it renders the molecule more water soluble and thus reduces their absorption and accelerates their excretion. A review of the genotoxicity and carcinogenicity data by Jung and coworkers (29) on a large number of aromatic aminosulfonic acids has confirmed that aromatic aminosulfonic acids, in contrast with some of their unsulfonated analogues, generally have no or very low genotoxic and tumorigenic potential. Conclusion While there are a number of approaches to reduce cancer risk of chemicals during their manufacture, processing, or use, including exposure reduction (30), the application of the growing knowledge on the mechanisms and structure-activity relationships to the development of products with lower carcinogenic potential appears to be a rational one. For some chemical classes such as the aromatic amine dyes, the structural and molecular basis of carcinogenicity is now known in considerable detail, thus providing opportunities for designing replacement dyes of lower carcinogenic potential. It is expected, however, that some of the dyes with the proposed structural modifications may possess different application properties. Therefore, the application properties of various replacement dyes may have to be examined and compared to determine which approach is the most appropriate for specific applications of the dyes. For the approximately 30 carcinogenic chemical classes that have been systematically reviewed, there are various metabolic activation pathways and somewhat unique structural requirements for carcinogenicity (rev. 4,11,31-33). With our increasing knowledge of the mechanisms and structure-activity relationships, it should be possible to develop safer products for other chemical classes using similar molecular design approaches. Disclaimer: The contents of this chapter have been presented in part at the Society of Toxicology 34th Annual Meeting, Baltimore, MD, March 1995. The views in this paper are solely those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. Mention of trade-names, commercial products or organizations does not imply endorsement by the U.S. government.


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