Basically, mechanism-based SAR analysis involves comparison of the chemical in question with structurally related compounds with known carcinogenic activity, identification of structural moiety(ies) or fragment(s) that may contribute to carcinogenic activity through a perceived or postulated mechanism, and evaluating the modifying role of the rest of the molecule to which the structural moiety/ fragment is attached. Since the pioneer work of the Millers (2), which conceptualized electrophiles as the ultimate carcinogen to interact with DNA to initiate carcinogenesis, considerable knowledge of the mechanisms of chemical carcino-genesis has accrued. 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. The knowledge of molecular mechanisms and other factors that affect carcinogenesis by various types of chemical carcinogens has established the basis for identifying suspect carcinogens by SAR analysis. The identification of structural features of elec-trophiles and their precursors has been a centerpiece for SAR prediction of genotoxic carcinogens that constitute the majority of known human carcinogens (3).
Except for some direct-acting carcinogens, most chemical carcinogens require metabolic activation to electrophilic species that bind covalently with nucleophilic sites in DNA to initiate carcinogenesis. The metabolic activation of chemical carcinogens by various metabolic systems has been reviewed (4). Table 1 lists examples of electrophilic species that are possible or probable ultimate carcinogens of a variety of chemical carcinogens. Some of the commonly encountered electrophiles or electrophilic intermediates in these chemical carcinogens include: carbonium ions (alkyl-, aryl-, benzylic), nitrenium and aziridin-ium ions, epoxides and oxonium ions, episulfonium ions, aldehydes, polarized double bonds (a,P-unsaturated carbonyls or carboxylates), peroxides, free radicals, acylating intermediates, quinone and quinoid intermediates. The structural
Table 1. Electrophilic Species of Some Chemical Carcinogens
Examples of carcinogens
Allylic carbonium ions
Benzylic carbonium ions
Formaldehyde a,p-Unsaturated carbonyls or carboxylates
Carbon-centered free radicals or radical cations
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