Covalent binding chemical structure

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

This procarcinogen undergoes metabolic conversion to benzo[a]pyrene diol epoxides, BPDEs (5,28-31), which have been the focus of structural and conformational studies by theoretical and experimental methods. These chemically reactive BPDEs are involved in covalent binding to DNA (13-22). 

Fig. 2 Schematic cartoon (a), and chemical structures (b) of the general fabrication procedure of a sensitive fluorescent monolayer on glass i) silanation of the glass slide with N-[3-(trimethoxysilyl)propyl]ethylenediamine to form the amino-terminated monolayer, ii) reaction with an amino-reactive fluorophore, iii) covalent attachment of a binding molecule...

In a similar biochemically oriented vein, several papers were published during 2003 in the journal Chemical Research in Toxicology, representing yet another area of applicability of 3 mm NMR probe capabilities. In the first of these reports, Hankin et al.159 described the results of an investigation into the covalent binding of leukotriene A4 to DNA and RNA. Later in 2003, Blair and co-workers160 reported on the characterization of 2 -deoxycytidine adducts derived from 4-oxo-2-nonenal, a novel lipid peroxidation product. Two of the adducts characterized, Ai and A2, were consistent with substituted ethano-deoxycytidine structures. The third adduct, B, was characterized as a 7-heptanone-etheno-deoxycytidine adduct (78). 

The toxicologist can still use of in silico technology36 to assess the chemical-based toxicity potential of various structural series and many molecular methodologies can still be applied, including covalent binding assays, mitochondrial assays and oxidative stress assays.29-37... 

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