6- pteridines

Pteridines serve as cofactors for a variety of enzyme-catalyzed reactions. The pteri-dine ring system has a pyrimidine fused at the 5,6-position of the pyrimidine ring to a pyrazine, while pterin refers to apteridine specifically substituted by an amino group at position 2 and a keto group at position 4. 

Folates are tripartite molecules comprising pterin, p-aminobenzoate (pABA), and glutamate moieties. In natural folates, the pterin ring exists in tetrahydro form (THF) or in 7,8-dihydro form (DHF). Tetrahydrofolates serve as cofactors in one-carbon transfer reactions during the synthesis of purines, formylmethionyl-tRNA, thymidy-late, pantothenate, glycine, serine, and methionine [313], 

In pteridines, we have a pyrimidine ring fused to a pyrazine ring. There are, of course, a number of possible ways of combining these two six-membered ring systems pteridines are pyrazino[2,3-fi(]pyrimidines (see Section 11.9). 

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

Folic acid (vitamin Bg) is a conjugate of a pteridine unit, p-aminobenzoic acid, and glutamic acid. Deficiency of folic acid leads to anaemia, and it is also standard practice to provide supplementation during pregnancy to reduce the incidence of spina bifida. 

Folic acid becomes sequentially reduced in the body by the enzyme dihydrofolate reductase to give dihydrofolic acid (FH2) and then tetrahydrofolic acid (FFi4). Reduction occurs in the pyrazine ring portion. 

Tetrahydrofolic acid then functions as a carrier of one-carbon groups for amino acid and nucleotide metabolism. The basic ring system is able to transfer methyl, methylene, methenyl, or formyl groups, and it utilizes slightly different reagents as appropriate. These are shown here for convenience, we have left out the benzoic acid-glutamic acid portion of the structure. These compounds are all interrelated, but we are not going to delve any deeper into the actual biochemical relationships. 

The pteridines are derived from the following ring system  

This nucleus is frequently substituted by hydroxy and amino groups and may carry an aliphatic side chain with one or three C-atoms. 2-Amino-4-hydroxy-pteridines are called pterins. 

1 Guanosine triphosphate cyclohydrolase I 2 pyrophosphorylase, phosphatase 3 diliydro-neopterin aldolase 4 hydroxymethyldihydropterin pyrophosphokinase 5 dihydropteroate synthase 6 dihydrofolate synthetase 7 dihydrofolate reductase 8 xanthine oxidase 

8-Dihydroneopterin is a branch point in pteridine metabolism. In the formation of tetrahydrobiopterin, sepiapterin, and isosepiapterin its three-carbon side chain is retained. In the biosynthesis of folic acid derivatives two carbon atoms are eliminated, whereas in the formation of xanthopterin and leucopterin the side chain is lost completely. 

In the formation of tetrahydrofolic acid 6-hydroxymethyl-7,8-dihydropterin pyrophosphate condenses with p-aminobenzoic acid (D 8.2) to dihydropteroic acid. This compound reacts with glutamine in the presence of ATP to dihydro-folic acid from which folic acid as well as tetrahydrofolic acid may be formed. 

Pyrazino[2,3-ti0pyr idines 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 butterflies (Lepidoptera). The pteridine ring system has subsequently been found in coenzymes which use tetrahydrofolic acid (derived from the vitamin folic acid) and in the cofactor of the oxomolybdoenzymes and comparable tungsten enzymes. It is also present in the anti-cancer drug Methotrexate. 

Pyridazines , Tishler, M. and Stanovnik, B., Adv. Heterocycl. Chem., 1968, 9, 211 Recent advances in pyridazine chemistry , ibid., 1979, 24, 363 Advances in pyridazine chemistry , ibid., 1990, 49, 385. 

Tautomerism and electronic structure of biological pyrimidines , Kwiatkowski, J. S. and Pullman, B., Adv. Heterocycl. Chem., 1975, 18, 200 Conversion of simple pyrimidines into derivatives with a carbon functional group , Sakamoto, T. and Yamanaka, H., Heterocycles, 1981, 15, 583. 

Nucleic acids in chemistry and biology , Eds. Blackburn, G. M. and Gait, M. J., Oxford University Press, 1996. 

Odor threshold of some pyrazines , Shibamoto, T., J. Food Sci., 1986, 51, 1098. 

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 

What compounds are produced at each stage in the following sequences (i) pyridazin-3-one reacted with POCI3 ( C4H3N2C1) and this with NaOMe (— CsH NaO) (ii) chloropyrazine with BUNH2/I2O °C (— C8H13N3). 

What are the structures of the compounds formed (i) C6H9IN2S from 3-methylthiopyridazine and CeHgClINa from 3-chloro-6-methylpyridazine, each with Mel (ii) C5H2CI2N2O from treatment of 

6-dichloropyrazine with LiTMP then HC02Et (hi) C14H12N2O2 from 2,6-dimethoxypyrazine with LiTMP, then h then PhC=CH/Pd(0). 

Interestingly, 2-phenylpteridine behaves differently. At —40°C the 1 1 adduct is formed, while at — 60 °C two adducts are present in the solution. One is the C-4 monoadduct, the other one is the 2 1 C-6/C-7 diadduct, as is proven by NMR spectroscopy. Oxidation of the mixture of the two adducts only gave 4-amino-2-phenylpteridine. Apparently the oxidation rate of the 1 1 adduct at C-4 is faster than the oxidation of the 2 1 diadduct, shifting the equilibrium between both adducts to the C-4 adduct. So the rate of the oxidation determines the ratio of the products obtained. 

Design and synthesis of new class of antitumor pteridine derivatives 90JHC1. 

---

Subsequent knowledge of the stmcture, function, and biosynthesis of the foHc acid coenzyme gradually allowed a picture to be formed regarding the step in this pathway that is inhibited by sulfonamides. The biosynthetic scheme for foHc acid is shown in Figure 1. Sulfonamides compete in the step where condensation of PABA with pteridine pyrophosphate takes place to form dihydropteroate (32). The amino acids, purines, and pyrimidines that are able to replace or spare PABA are those with a formation that requkes one-carbon transfer catalyzed by foHc acid coenzymes (5). 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

The spectra of protonated polyaza heterocycles are frequently complicated by the occurrence of covalent hydration. This is more common with polycyclic systems, e.g. pteridine. 

Pyrimidines from pteridines and related fused systems... 

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-... 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

The mass spectra of pyridopyrimidines in general show many features in common with those of other related N-heterocycles, in particular quinazolines and pteridines. The pyridopyrimidines show strong molecular ions, and when breakdown of the hetero ring occurs, fragments arising from loss of CO, CN, HCN and HCNO are observed. 

Amino groups a to nitrogen are hydrolyzed to the corresponding oxo compounds (as in the purines and pteridines) in bo h acid and alkaline conditions. Schiff bases are reduced to benzylamino derivatives with borohydride. 

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). 

The only reaction of this type noted involved the reaction of pteridines, e.g. (415), with malonodinitrile (or cyanoacetamide), via ring opening to (416), with final [6 + 0 ( )] cyclization to give the 6-amino-7-nitrile (amide) (417) (73JCS(P1)1615, 73JCS(P1)1974). 

By far the most important reaction for the synthesis of pyridopyrazines is the reaction of diaminopyridines with two-carbon fragments, the pyridopyrazine equivalent of the well-known Isay reaction in the pteridine field. 

The pyridopyrazine group does not contain any actual natural products, but the considerable scope for synthesis of 1- and 3-deaza analogues of various natural pteridines or pteridine drugs has been widely exploited. 

Synthetic Pteridines with Chemotherapeutic Effects Folic Acid and Related Derivatives... 

The basic pteridine nucleus (1) consists, according to X-ray crystallographic studies (75JCS(P2)40), of a more or less planar molecule with no unexpected features in so far as... 

Studies on covalent hydration of N-heterocycles (67AG(E)919,76AHC(20)117) have revealed the diagnostic value of alkyl substituents in structural assignments due to their steric hindrance effects in addition reactions. C-Methyl substituents are therefore also considered as molecular probes to solve fine-structural problems in the pteridine field. The derivatives... 

---