Peroxisome proliferators chemical structure

Inducers of cytochromes P450 IV that are involved in peroxisome proliferation, which brings about carcinogenicity in rodents, are quite difficult to identify using COMPACT. However, because these chemicals usually possess an acidic function, or an isostere, combined with at least one aromatic ring in a specific orientation relative to the acid moiety, it is possible to predict potential peroxisome proliferators by structural analogy with known inducers such as... 

Highly sensitive targeted lipidomic approaches are rapidly leading to the identification of new analogs of anandamide (Tan et al., 2006). The two major families of lipids that share common chemical structure with anandamide are FAEs and fatty acid amides. Although many of these lipids show no activity at CB receptors, they are known to bind and activate other receptors, such as transient receptor potential vanilloid type-1 (TRPV-1) and the nuclear receptor peroxisome proliferator-activated (PPAR-a). 

Currently, over 100 compounds have been identified as PPs. The literature indicates that induction of peroxisome proliferation is not limited to exogenous chemicals. A number of endogenous substances, such as the steroid hormones, thyroid hormones, mor-phogenes, and fatty acids, are also involved in peroxisome proliferation. Peroxisome proliferation in hepatic parenchymal cells of rats and mice following the administration of clofibrate has been reported by numerous investigators. Compounds that are structurally unrelated to clofibrate, such as acetaminophen and Wy-14,643, can also cause peroxisome proliferation (Table 1). The industrial solvent trichloroethylene, the industrial plasticizers dill-ethyl hexyl) phthalate (DEHP) and di(2-ethyl hexyl) adipate (DEHA), have also been found to be hepatic peroxisome proliferators. 

Fig. 1. Chemical structures of different fibrate drugs known to be peroxisomal proliferators (PP) and of neuroactive drugs. Note that WY-14,643 is a fibrate drug and a potent PP but is not used clinically.

The SAR of peroxisome proliferators has been reviewed ((Bentley et al. 1993 Lai 2004 Lake and Lewis 1993 Woo and Lai 2003)). Figure 20.1 shows the chemical structures for a variety of hepatocarcinogenic peroxisome proliferatiors. However, at first glance the chemical structures appear to be diverse. From the mechanistic point of view, there are two common features (a) firtually aU the... 

Thia fatty acids have been used as tools in experimental models to further penetrate the mechanisms of the lipid metabolism. These fatty acids are activated to their respective CoA-esters, but, they cannot be degraded by 3-oxidation because of the sulfur substitution in 3-position (reviewed ). Tetradecylthioacetic acid (TTA), a representative member of the 3-thia family, has the chemical structure of palmitic acid (C16) in which a sulfur atom is located between the 2 and 3-carbon atoms (COOH-CH2-S-(CH2)i3-CH3). TTA is a novel hypolipidemic drug which has been shown to combine several effects of CO-3 PUFAs, such as EPA, and structurally unrelated peroxisome proliferators, such as phenylacetate and fibrates. From this perspective we wanted to investigate if TTA shares the antitumor activity found for these functionally related compounds, and furthermore to study the metabolic effects of TTA in cancer cells in relation to the effects found in hepatocytes. 

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