Pteridines, reduction

Most pteridines are degraded to pyrazines and when they do yield pyrimidines, these may well be the ones from which they were made. However, some useful preparations of pyrimidines from pteridines are known. Thus, reduction of pteridin-7(8//)-one (732) and subsequent hydrolysis yields N-(4-aminopyrimidin-5-yl)glycine (733) (52JCS1620) and hydrolysis of 5,8-dimethylpteridine-6,7(5Ff,8Ff)-dione (734) gives dimethyl-... 

Apart from the nuclear bromination observed (Section 2.15.13.1) in the attempted radical bromination of a side-chain methyl group leading to (396), which may or may not have involved radical intermediates, the only other reaction of interest in this section is a light-induced reduction of certain hydroxypyrido[3,4-f)]pyrazines or their 0x0 tautomers analogous to that well-known in the pteridine field (63JCS5156). Related one-electron reduction products of laser photolysis experiments with 1 -deazaflavins have been described (79MI21502). 

Radical anions have recently been detected during electrochemical reductions of lumazines (80H(14)1603) and are also assumed to be reactive intermediates in the reductive acylation of 2,4-disubstituted pteridines to the corresponding 5,8-diacyl-5,8-dihydro derivatives. 

Pteridine, 6-oxo-5,6,7,8-tetrahydro-electrochemistry, 3, 285 Pteridine, 7-oxo-5,6,7,8-tetrahydro-electrochemistry, 3, 285 Pteridine, 2-phenyl-structure, 3, 266 Pteridine, 4-phenyl-structure, 3, 266 Pteridine, 7-phenyl-oxidation, 3, 305 Pteridine, 2,4,6,7-tetraamino-synthesis, 3, 291 Pteridine, 2,4,6,7-tetrabromo-reactions, 3, 291 Pteridine, 2,4,6,7-tetrachloro-hydrolysis, 3, 291 properties, 3, 267 Pteridine, 1,2,3,4-tetrahydro-structure, 3, 280 Pteridine, 5,6,7,8-tetrahydro-reduction, 3, 280 synthesis, 3, 305 Pteridine, 2,4,6,7-tetramethyl-NMR, 3, 266... 

Pteridine-6,7-dione, 4-amino-2-chloro-chlorination, 3, 296 Pteridine-6,7-dione, 2,4-dichloro-synthesis, 3, 291 Pteridine-6,7-dione, 5-hydroxy-synthesis, 3, 316 Pteridine-6,7-dione, 8-methyl-reduction, 3, 298 Pteridine-2,6-diones structure, 3, 272 Pteridine-4,6-diones structure, 3, 272 synthesis, 3, 310 Pteridine-6,7-diones reduction, 3, 298 synthesis, 3, 316... 

Pteridin-6-one, 2-chloro-7,8-dihydro-reduction, 3, 293 Pteridin-6-one, 7,8-dihydro-oxidation, 3, 307 structure, 3, 279 Pteridin-6-one, 7-methyl-2,4-disubstituted synthesis, 3, 310 hydroxylation, 3, 287... 

Leucovorin, since it is totally reduced, is polarographically inert in a pH 9 buffered solution.63 After acid treatment, three polarographic waves are generated, corresponding to an anodic oxidation of a tet-rahydro compound and two cathodic reductions of unreduced pteridines presumably at least one of these three is a dihydro species. Polarography is useful as a technique in structural elucidation, but analytical data would be difficult to obtain from an acid-treated solution containing several species, each with its own polarographic behavior. 

The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems. 

Reductive sequences involving flavoproteins may be represented as the reverse reaction, where hydride is transferred from the coenzyme, and a proton is obtained from the medium. The reaction mechanism shown here is in many ways similar to that in NAD+ oxidations, i.e. a combination of hydride and a proton (see Box 11.2) it is less easy to explain adequately why it occurs, and we do not consider any detailed explanation advantageous to our studies. We should register only that the reaction involves the N=C-C=N function that spans both rings of the pteridine system. 

Folate, the anion of folic acid, is made up of three different components—a pteridine derivative, 4-aminobenzoate, and one or more glutamate residues. After reduction to tetrahydrofolate (THF), folate serves as a coenzyme in the Q metabolism (see p. 418). Folate deficiency is relatively common, and leads to disturbances in nucleotide biosynthesis and thus cell proliferation. As the precursors for blood cells divide particularly rapidly, disturbances of the blood picture can occur, with increased amounts of abnormal precursors for megalocytes megaloblastic anemia). Later, general damage ensues as phospholipid... 

The importance of the dihydro and tetrahydro oxidation states of pterins in biology has stimulated interest in the study of the chemical properties of these compounds, especially with respect to electron-transfer and radical reactions. It has become apparent, perhaps unsurprisingly, that the stability and reactivity of these oxidation states are very sensitive to substituent effects and the much greater stability of the fully conjugated pteridines is most evident. The oxidation of tetrahydropterins and the reduction of dihydropterins have become especially important in the chemistry of nitric oxide production in nature and in oxidative stress but the accumulation of relevant facts has not led so far to a detailed understanding of the chemical property relationships. Relevant information is summarized in the following section. 

In modern medicinal chemistry, the creation of diversity on a structural framework is important. In principle, diversity at positions 2, 4, 6, 7, and 8 of pteridines can be achieved using such solid-phase chemistry. This prototype solid-phase synthesis involved nitrosation of the resin-bound pyrimidine, reduction of nitroso group with sodium dithionite, and subsequent cyclization with biacetyl to afford pteridines 114 and 115. Cleavage from the resin by nucleophilic substitution of the oxidized sulfur linker using w-chloroperbenzoic acid or DMDO led to the pteridine products 116 and 117 (Scheme 23). 

O -Benzylfolates, such as 230, have been investigated as inhibitors of DNA allyltransferase with some promise <2004JME3887> they can readily be prepared from 2,5,6-triamino-4-0-benzylpyrimidine by standard ring-forming condensation via the pteridine 6-aldehyde and reductive amination to insert the 4-aminobenzoyl glutamate. 

The electrolytic reduction of purines and pteridines in aqueous acidic medium was treated in Part I and is discussed in Ref. 5. In aprotic media 6-substituted purines are reduced to a dimer353 in a one-electron reaction, whereas in the presence of a proton donor the reduction resembles that in aqueous media.302... 

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