Toxicophores

Williams DP, Park BK. Idiosyncratic toxicity the role of toxicophores and bioactivation. Drug Discov Today 2003 8 1044-50. 

Toxicophores [33] (polycyclic aromatic and polycyclic planar systems, nitro-and amino-aromatics). 

Kazius, J., McGuire, R., Bursi, R. Derivation and validation of toxicophores for mutagenicity prediction. J. Med. 

Figure 8.15), were devoid of such toxicity. As for many of the agents featured in this section the structural similarity between carbutamide and tolbutamide clearly implicates the anilino function as the toxicophore. 

Table 8.2 gives a summary of the various toxicities and the stages at which they can occur. Also summarized are the causes for the specificity of the effect. With mutagenicity, certain pre-clinical toxicity, carcinogenicity and late clinical toxicology, the actual structure of the molecule is important and care should be taken to avoid the incorporation of toxicophores into compounds, as outlined about. Direct toxicity is addressed by ensuring the daily dose size is low, the intrinsic selectivity high and the physicochemical properties within reasonable boundaries. 

Toxicophore analysis Evaluation of chemical moieties historically associated with safety issues, for example, genotoxidly, cationic amphiphilic drugs and phosphohpidosis, tertiary amines that are charge neutral at physiologic pH and vacuohzation... 

Genotoxicity Evaluation by toxicophore analysis and Ames type muta-gendty test and chromosomal toxidty such as in vitro micronudeus test by HCA [21—23]... 

For many of the drugs associated with hepatotoxicity, there are examples of structurally related drugs which are latent to bioactivation and toxicity because of the absence of the toxicophore or the existence of alternate metabolic pathways. For example, the hepatotoxicity associated with the use of the anti-Parkinson s agent tolcapone does not occur with the structurally related drug entacapone, despite administration at doses similar to tolcapone (200-1000 mg QD). This disparity may be explained in part by the observation that entacapone does not succumb to the bioactivation reactions of tolcapone in humans (Scheme 15.3) [35]. It is also noteworthy that tolcapone but not entacapone is a potent uncoupler of oxidative... 

Figure 15.1 Compilation of structural alerts/toxicophores known to undergo bioactivation and examples of hepatotoxic drugs containing the structural alerts.

Structural Fragments of a Drug Molecule Pharmacophore, Toxicophore, Metabophore... 

The multiphore method concepmalizes a dmg as being constmcted in a modular fashion from bioactive subunits, or biophores. Since a dmg is invariably composed of many biophores, it is a multiphore. The most important biophore within the dmg stmcture is the pharmacophore, the subset of atoms within the dmg that permits energetically favorable binding to the receptor site with the elucidation of a subsequent beneficial biological response. Other portions of the molecule determine the metabolic and toxicological properties of the dmg these are the metabophores and toxicophores, respectively. 

Examples of toxicophores found in commercial chemicals, along with the toxic effects often caused by chemicals that contain these toxicophores, are shown in Table 4.1 and discussed in the cited references [1-17]. Many more examples can be found in the literature [18-23]. Chemists should try to avoid incorporating structural substituents associated with causing toxic effects. If a toxicophore is required for use function, the chemist should attempt to identify molecular modifications that will mitigate the concern for the toxicophore but that will not affect its use efficacy. Examples of such modifications are discussed elsewhere in this chapter. 

Table4.1 Examples of toxicophoric substituents encountered in commercial substances, and the resulting toxicity often caused by chemicals that contain these toxicophores .

Table 4.2 Examples of electrophilic toxicophores commonly encountered in commercial substances, the reactions they undergo with biological nucleophiles, and the resulting toxicity3. ... 

Medicinal chemists have used isosterism for the design of safe, effective drug substances for many years. During the development of anti-ulcer medications, for example, it was found that metiamide (38) greatly reduced acid secretion in the gastrointestinal tract by antagonizing H2-receptor sites. Its potential as auseful anti-ulcer medication was lessened by adverse effects caused by the thiourea moiety, a toxicophore (Table 4.1). This moiety is essential for H2-receptor blockade, but bestows toxicity. 

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