Pteridine ring system

We do not want to consider the chemistty of the pteridine ring system here, but instead we... 

The pteridine ring system is composed of fused pyrazine and pyrimidine rings, either of which might be attacked by a complex metal hydride. The reaction of pteridine (145), 2,4-dichloropteridine (146), or 2,4-dimethoxypteridine (147) with lithium aluminum hydride was reported to occur with reduction of the pyrazine ring to give the 5,6,7,8-tetrahydropteridine (148-150, respectively).150... 

More information about the mechanism of the Viscontini reaction has been collected from model studies condensing 4,5,6-triamino-2-methylthiopyrimidine (338) in a similar manner with the phenylhydrazones of l- (339) and D-arabinose and omitting the iodine oxidation step (Scheme 55). Under these conditions an interesting intermediate, consisting of a tricyclic pteridine ring system (341), was formed by intramolecular adduct formation of the trihydroxypropyl sidechain on to the 7-position of the 5,6-hydropteridine precursor (340) (Scheme 55). The main reaction product could be crystallized and the structure unambiguously proven by an x-ray analysis <90HCA808). 

The known chemistry is almost entirely limited to the fully conjugated systems which have received a great deal of attention in recent years. Most systems are readily available and a number of these have been prepared for biological purposes. Others like the furazano[3,4-cf]pyrimidines can be used as intermediates in the preparation of purine or pteridine ring systems. 

A closer look at these events reveals that bacteria synthesize folic acid using several enzymes, including one called dihydropteroate synthetase, which catalyzes the attachment of p-aminobenzoic acid to a pteridine ring system. When sulfanilamide is present it competes with the p-amino-benzoic acid (note the structural similarity) for the active site on the enzyme. This activity makes it a competitive inhibitor. Once this site is occupied on the enzyme, folic acid synthesis stops and bacterial growth stops. Folic acid can also be synthesized in the laboratory. ... 

The reduction of pyrazine[2,3-c ]pyriniidines, the pteridine ring system, usually occurs in the pyrazine ring to yield dihydro and tetrahydro derivatives. The reduction of 1- and 3-methyl-6,7-diphenylpteridin-4-one with NBH gives no isolable products, whereas 3,4-dihydro-l,3-dimethyl-6,7-di-phenyl-4-oxopteridinium iodide (438) gives the 1,2,3,4-tetrahydro product 439 200 jhe reduction of pteridine (440) itself with NBH occurs readily in trifluoroacetic acid, giving two products in 94% overall yield. 1,2,3,4-(441) and 5,6,7,8-tetrahydropteridine (442) were obtained in 38 and 58% yields, respectively. The pyrazine ring is preferentially reduced. 

This enzyme also catalyzes conversion of dihydrofolate (FH2) to tetrahydrofolate (FH4), and folic acid contains a pteridine ring system (see the discussion of one-carbon metabolism in Chapter 27). However, regeneration of tetrahydrobiopterin by the dihydrofolate reductase reaction, however, is too slow to support normal rates of phenylalanine hydroxylation. 

Pyrazino[2,3-d/]pyrimidines are known as pteridines , because the first examples of the ring system, as natural products, were found in pigments, like xanthopterin (yellow), in the wings of bntterflies (Lepidoptera). The pteridine ring system has subsequently been found in coenzymes that use tetrahydrofolic acid (derived from the vitamin folic acid), and in the cofactor of the oxomolybdoenzymes and comparable tungsten enzymes. 

The synthesis of the pteridine ring system has been approached by two obvious routes one is the fusion of the pyrazine ring onto a pre-formed 4,5-diamino-pyrimidine, and the second, the elaboration of the pyrimidine ring on a pre-formed pyrazine. The first of these, the Isay synthesis, suffers from the disadvantage that condensation of the heterocyclic 1,2-diamine with an unsymmetrical 1,2-dicarbonyl compound... 

Vitamins are substances essential for a healthy life humans must ingest vitamins via their diet because there is no mechanism for their biosynthesis in the body. There are 14 vitamins - the name was coined when the first vitamin chemically identified (vitamin Bi in 1910) turned out to be an amine - a vital amine. A typical vitamin is folic acid, a complex molecule in which the functionally important unit is the bicyclic pyrazino[2,3- f pyrimidine (pteridine) ring system, and its arylaminomethyl substituent. Folic acid is converted in the body into tetrahydrofolic acid (FH4) which is crucial in carrying one-carbon units, at various oxidation levels, for example in the biosynthesis of purines, and is mandatory for healthy development of the foetus during pregnancy. Other essential co-factors that contain pteridine units must and can be biosynthesised in humans - without them we cannot survive - aud are incorporated into oxygen-transfer enzymes based on molybdenum, in which the metal is liganded by a complex ene-dithiolate. 

The first synthesis of the pteridine ring system 1 was separately reported by Wohler1 and... 

Figure 2.1 Numbering systems for pterin, a derivative of the pteridine ring system (top), in an uncyclized and fully reduced form initially proposed for Moco (middle) and as the cyclized and reduced pyranopterin form observed by crystallography in the majority of molybdenum enzymes (bottom).

Pteridines a group of compounds containing the pteridine ring system (Fig.). The majority of naturally occurring P. are chemically related to pterine (Fig.). A smaller number are derived from lumazine (Fig.). Both folic acid [see Tetrahydrofolate Vitamins (Bj complex)] and Tstrahydrobiopterin (see) are P. and serve as hydrogen transfer cofactors. Folic acid is a vitamin for mammals, but they are able to synthesize tetrahydrobiopterin in spite of their chemical similarity, these compounds are synthesized by different pathways. 

The cleavage of heteroaryl sulfones from polymeric supports can be achieved by reaction with azide ions. Suckling el al. applied this strategy to the synthesis of pteridines. In fact, the starting pyrimidine was linked to polystyrene via a thioether 214. After con-stmction of the pteridine ring system, the activation of the sulfur linker by oxidation to the sulfone with dimethyldioxirane followed by nucleophilic substitution with sodium azide affords the target molecule 218 in 41% overall yield (Scheme 3.30). 

For the (rare) case where the 3-D structure of the receptor/inhibitor complex is known, the conformation of the inhibitor can directly be used to build a 3-D pharmacophore. For methotrexate, it is known that the pteridine ring system is... 

Folic acid is essential to human life. Its structure incorporates a 1,3,5,8-tetraazanaphthalene (pteridine) ring system, together with 4-aminobenzoic acid (Section 15-4) and (S)-aminopentanedioic (glutamic) acid (Section 26-1). Folic acid is necessary for the proper development of the nervous system in the very early stages of pregnancy. One of its functions is the transfer of one-carbon fragments between... 

Amino-l,3-dimethyl-5-nitrosouracil (270), reported last year as a highly versatile precursor for the purine and pteridine ring systems, has again found use (Scheme 63) in a new synthesis of 6-hydroxy-pteridines (271). Photo-decomposition of 6-azido-l,3-dimethyluracil as a solution in a secondary or primary amine has been used as a convenient method of preparing 6-alkylamino-5-amino-uracils. The procedure has now been extended ... 

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