Hydroxamic acids chemical reactivities

The enzyme can also catalyze the transfer of an acetyl group from an N-acetylated hydroxylamine (hydroxamic acid) to form an acetoxy product, i.e., an N to O transacetylation and this pathway does not require acetyl Co-A (12). A-hydroxy-4-acetylaminobiphenyl provides an example of this conversion as shown in Figure 7.7. The significance of this pathway is that it leads to the activation of the hydroxamic acid because acetoxy derivatives of aromatic amines are chemically reactive and many are carcinogens such as the heterocyclic amines formed when meat is heated to a high temperature, e.g., 2-amino-1-mcthyl-6-phenylirnidaz()[4,5-i ]pyri(linc. 

TABLE 14. Results of correlations for chemical reactivities of hydroxamic acids ... 

There is some evidence that the form of the chemical carcinogen that ultimately reacts with cellular macromolecules must contain a reactive electrophilic center, that is. an electron-deficient atom that can attack the numerous electron-rich centers in polynucleotides and proteins. As examples, significant electrophilic centers include free radicals, carbonium ions, epoxides, the nitrogen in esters of hydroxylamines and hydroxamic acids, and some metal cations. It is believed that carcinogens, which in themselves are not electrophiles, are metabolized to electrophilic derivatives that then become the ultimate" carcinogens. 

This family of enzymes is cytosolic and is widely distributed in a variety of mammalian tissues. There are also enzymes that hydrolyze N-substituted acetamides (i.e., amidases, as described previously) and the extent to which free versus acetylated amines are present in vivo depends on the relative rates of the acetylation and deacetylation reactions, on the physical and chemical properties of the two products, and whether or not the amine is metabolized by competing pathways. Some acetylated hydroxamic acids are chemically reactive and appear to be ultimate carcinogens. 

First of all, natural products with functional groups associated with chemical reactivity or toxicity can be discarded. For example, many are phenolic, and these are generally impromising because they are prone to oxidation and conjugation within a plant. Quinones and other redox-reactive compoimds are also unattractive, as are natural products which are likely to be metal-chelators, such as hydroxamic acids and catechols. 

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