Quinones biological effects

The distinguishing feature of tyrosinase is that it catalyzes the oxidation of monohydric phenols, like tyrosine, to the dihydric form and dihydric phenols, like DOPA and catechol, to the corresponding quinones. The striking biological effects of this enzyme arise from quinones which polymerize to produce the darkening of various plants on injury and melanin in mammals. The relative oxidation rates of several dihydric phenols by tyrosinase are given in Table III. 

The biological effects of quercetin are believed to result from its antioxidant properties. Recently, it was clearly demonstrated that quercetin could function both as an antioxidant and a prooxidant, depending on concentration and free radical sources and their location in the cell. Also, quercetin was observed to be cytotoxic in a dose-dependent manner. Although the exact mechanism of cytotoxicity has not yet been fully elucidated, it may involve formation of 02 or its metabolite o-quinone (Fig. 7). Such species are known to be toxic and to bind irreversibly to various cell constituents by covalent binding with sulfhydryl groups or other essential groups. 

It should be noted that to date the o-qninone/ROS mechanism has only been described in vitro. There are no reports that that PAH o-qninones are formed in vivo from B[a]P and are stable enough to redox cycle and indnce ROS. B[a]P-7,8-qninone has been the most intensely studied o-quinone and has been fonnd to addnct to DNA in vitro (Balu et al. 2004, 2006), bnt not in vivo (Nesnow et al. 2005). B[a] P-7,8-qninone induces DNA breaks (Park et al. 2008) and indnces ROS in vitro (Flowers-Geary et al. 1996). Current thonght is that B[a]P-7,8-qninone mediates its in vitro biological effects through ROS formation in vitro. 

The structural design of 68 seems to be the key to the problem. In fact, an electrochemical study has shown that the biological effect seems triggered by the reversible oxidation of the ferrocene entity, which could then be followed by a premature transformation of the phenol via generation of an intermediate carbenium ion, leading to a fairly stable quinone methide 70 [94], It is well documented that electrophilic species such as quinone methides have the potential to alkylate cellular macromolecules to produce a cytotoxic effect [151-153]. Complex 69, however, which is isolated in the form of the stable trans isomer, cannot produce a stabilized quinone methide. It is thus clear that for targeted organometaUic products such as 68 and 69, structural considerations come to the fore. 

To assess the trapping of biological nucleophiles, the pyrido[l,2-a]indole cyclopropyl quinone methide was generated in the presence of 5 -dGMP. The reaction afforded a mixture of phosphate adducts that could not be separated by reverse-phase chromatography (Fig. 7.16). The 13C-NMR spectrum of the purified mixture shown in Fig. 7.16 reveals that the pyrido [1,2-a] indole was the major product with trace amounts of azepino[l,2-a] indole present. Since the stereoelec-tronic effect favors either product, steric effects must dictate nucleophilic attack at the least hindered cyclopropane carbon to afford the pyrido[l,2-a]indole product. Both adducts were stable with elimination and aromatization not observed. In fact, the pyrido [1,2-a] indole precursor (structure shown in Scheme 7.14) to the pyrido [l,2-a]indole cyclopropyl quinone methide possesses cytotoxic and cytostatic properties not observed with the pyrrolo [1,2-a] indole precursor.47... 

From the biological point of view, the effect of anaerobiosis has been characterized in purely anaerobic, facultative anaerobic, and aerobic bacteria, in yeasts, and in tissues from higher organisms [6-12], From these studies it can be deduced that almost every azo compound can be biologically reduced under anaerobic conditions [4]. Reduced flavins are produced by cytosol flavin-dependent reductases [6, 13], while quinone reductase activity located in the plasma membrane [14] and extracellular azo reductase activities [9, 15] were also observed. 

One example of the effect of substitution on biological potency involves the popular drug acetaminophen (Tylenol ). Acetaminophen is almost completely metabolized in the liver with the production of harmless products that are excreted through the kidneys. A small amount of the drug maybe metabolized, however, to a toxic product, N-acetyl-p-henzo-quinone imine. In cases where large quantities... 

Wurster in 1879 had already prepared crystalline salts containing radical cation 23 (equation 12). Subsequently, radical cations of many different structural types have been found, especially by E. Weitz and S. Hunig, and recently these include a cyclophane structure 24 containing two radical cations (Figure 3). Leonor Michaelis made extensive studies of oxidations in biological systems, " and reported in 1931 the formation of the radical cation species 25, which he designated as a semiquinone. Michaelis also studied the oxidation of quinones, and demonstrated the formation of semiquinone radical anions such as 26 (equation 13). Dimroth established quantitative linear free energy correlations of the effects of oxidants on the rates of formation of these species. ... 

Puupehenone (63) is a member of a distinctive family of sponge metabolites — a sesquiterpene joined to a C6-shikimate moiety — first exemplified by the quinol-quinone pair of avarol and avarone. Among the varied activities that have been reported for this diverse class of compounds is the property of ilimaquinone to inhibit replication of the HIV virus.78 Preliminary screening of puupehenone against Mycobacterium tuberculosis showed 99% inhibition of the organism. A series of chemical modifications have been conducted on puupehenone to study the effect on its biological activity. 

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