Radical Phosphate centered

The proposed mechanism for the inactivation of RDPR by tezacitabine is detailed in Figure 7.58. Conversely to the radical A generated from the cytidine phosphate, the radical A formed from the 2 -fluoromethylene-2-deoxycytidine cannot eliminate a water molecule (Figures 7.57 and 7.58). It undergoes an isomerization into a new radical B centered on the fluorine-substituted carbon. This latter finally provides, after several steps, a high electrophilic entity D able to add the subunit Rj of the enzyme. The resulting covalent adduct of D with the enzyme has been identified. ... 

The chemistry of radical sites adjacent to phosphatoxy centers elicited interest because of the involvement of such species in DNA degradation processes. These species can give rise to rearrangement, elimination, and substitution products, and for some time concerted eliminations and migrations as well as heterolysis to a radical cation and a phosphate anion were considered to be involved (Scheme 2). Recently, experimental studies of the l,2-dibenzyl-2-(diphenylphosphatoxy)-2-phenylethyl radical and complementary theoretical studies of l,l-dimethyl-2-(dimethylphosphatoxy)ethyl radical have been interpreted as indicating that a radical cation/anion pathway with initial formation of 49 is favored. ... 

The phosphate-adduct radical is also formed, when the reaction is initiated by S04 [reaction (18)] in the presence of phosphate ions (Behrens et al. 1988). This may either be due to an Sn2 substitution reaction [reaction (19)] or a reaction of the phosphate ion with the radical cation [reaction (17)] formed either by an elimination of S042- plus H+ [reaction (20)] and subsequent protonation of the N(3)-centered radical [equilibrium (22)] or by S042- elimination [reaction (21)], as envisaged originally. The reaction of the radical cation with phosphate would then give rise to the observed radical [reaction (23)]. 

Triazine (e.g., atrazine, simazine) and substituted urea (e.g., diuron, monuron) herbicides bind to the plastoquinone (PQ)-binding site on the D1 protein in the PS II reaction center of the photosynthetic electron transport chain. This blocks the transfer of electrons from the electron donor, QA, to the mobile electron carrier, QB. The resultant inhibition of electron transport has two major consequences (i) a shortage of reduced nicotinamide adenine dinucleotide phosphate (NADP+), which is required for C02 fixation and (ii) the formation of oxygen radicals (H202, OH, etc.), which cause photooxidation of important molecules in the chloroplast (e.g., chlorophylls, unsaturated lipids, etc.). The latter is the major herbicidal consequence of the inhibition of photosynthetic electron transport. 

The first one electron oxidation produces a radical cation on the sugar phosphate (SP +). The radical cation subsequently deprotonates yielding a neutral carbon centered radical SP(-H). The second oxidation involves an electron transfer from SP(-H) to a nearby guanine radical cation G +. This step requires that the hole on the guanine have some mobility. It is known that a hole located on guanine at 4K is mobile, with a range of ca. 10 base pairs [76], The result of this second oxidation is a a deoxyribose carbocation SP(-H)+. 

C3 center of deoxyribose. Due to stereochemical reasons a similar configuration cannot be realized in the 5 -phosphates of pyrimidines. Finally, the distribution of SOMO in the CX -O fragments indicates that the radical resides on the CX atom of deoxyribose moiety and consequently the excessive charge is localized on the phosphate group (Figure 21-28). 

To obtain an even better model compound for the corresponding deoxyribose-centered radical in DNA, ether phosphates were used instead of the alcohol phosphates described in reaction 23. For example, on reaction of OH with 2-methox-yethylphosphate at pH 4.5 the 2-yl radical is the most prominent species (see Scheme 10), as observed by ESR [89]. By measuring the coupling constants as a function of pH, the pATa of the radical was determined to be 6.5. On reducing the pH, the 2-yl radical disappeared giving rise to two product radicals, as shown below (Scheme 10). 

Figure 10 Model systems used for various ring-breaking sugar radicals radicals observed experimentally (I and II), model ring-breaking radical (M), C5 centered radical proposed experimentally (IV) and the model ring-breaking radical with a phosphate group (V).

Three of the deoxyribose carbon centered radicals, dRib(C3 -H), dRib(C4 -H), and dRib(C5 -H), give rise to prompt SSB via a phosphate elimination reaction. The strand break mechanism for the dRib(CI -H) radical differs substantially. Like the three radicals above, it will release a free unaltered base but instead of forming a strand break, a subsequent one-electron oxidation results in deoxyribonolactone (dRibonoLac) formation (Fig. la) [1,18].This abasic site is quite stable. Heat and a catalyst, such as spermine, turn this lesion into a strand break plus 5-methylenefuranone (SMFur) [18]. The later is a signature end product of Cl sugar damage. 

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