Pteridines as Substrates

Although pteridines can be made from pyrazines, it is usually much easier to prepare them from 4,5-pyrimidinediamines or the like.1689 Since many pteridines can be easily degraded to pyrazines, this process offers a practical primary synthetic route to a variety of pyrazine derivatives. However, in comparison with more than 150 examples cited by Barlin from pre-1978 literature,1686 recent use of the method has been modest. Typical examples follow  

7-Methyl-2,4(177, 377)-pteridinedione (107) gave 3-amino-5-methyl-2-pyrazinecar-boxylic acid (108) (4M NaOH, reflux, 20 h 30%).693 

Primary Syntheses from Other Heterocyclic Systems 

2-Amino-6-/ - (1,3-dicarboxypropyl )carbamoyl]anilinomcthyl-4(3//)-ptcridinonc (folic acid 109) gave 3-amino-6-/ -carboxyanilinomcthyl-2-pyrazinccarboxylic acid (110) (2.5 M KOH, reflux, N2,96 h 87%).769 

4-Pteridinamine 3-oxide (115, R = H) gave 3-(hydrazonomethyl)amino-2-pyrazinecarboxamide oxime (116, R = H) (H2NNH2.H20, MeOH, 20°C, 4 h 85%) the 2-phenylated substrate (115, R = Ph) likewise gave 3-(a-hydra-zonobenzyl)amino-2-pyrazinecarboxamide oxime (116, R = Ph) (20°C, 2 h then reflux, 30 min 66%).353 

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B29. Bergmann, F., and Kivietny, H., Pteridines as substrates of mammalian xanthine oxidase. Biochim. et Biophys. Acta. 33, 29-46 (1959). 

Palladium-mediated cross-coupling reactions in pteridine chemistry provide for variation at position 6 using halogenated pyrazines or pteridines as substrates (see Section 10.18.7.4). The 6-bromopyrazine 168 is a versatile intermediate leading to pteridine 169 both compounds have been shown to be substrates for palladium-mediated cross-coupling reactions <2000J(P1)89> (Scheme 32). 

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

Among its inhibitors are methotrexate (MTX), trimethoprim, and other derivatives of pyrimidines, triazines, pteridines, and related heterocyclic compounds. Some of these inhibitors, such as MTX, bind more tightly to Escherichia coli enzyme than does the substrate dihydrofolate. This fact has been attributed to ion-pair formation between protonated MTX and a negative carboxyl, presumably Asp-27, as well as to hydrophobic interactions.33... 

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. 

Free tryptophan is transported into the brain and nerve terminal by an active transport system which it shares with tyrosine and a number of other essential amino acids. On entering the nerve terminal, tryptophan is hydroxylated by tryptophan hydroxylase, which is the rate-limiting step in the synthesis of 5-HT. Tryptophan hydroxylase is not bound in the nerve terminal and optimal activity of the enzyme is only achieved in the presence of molecular oxygen and a pteridine cofactor. Unlike tyrosine hydroxylase, tryptophan hydroxylase is not usually saturated by its substrate. This implies that if the brain concentration rises then the rate of 5-HT synthesis will also increase. Conversely, the rate of 5-HT synthesis will decrease following the administration of experimental drugs such as para-chlorophenylalanine, a synthetic amino acid which irreversibly inhibits the enzyme. Para-chloramphetamine also inhibits the activity of this enzyme, but this experimental drug also increases 5-HT release and delays its reuptake thereby leading to the appearance of the so-called "serotonin syndrome", which in animals is associated with abnormal movements, body posture and temperature. 

In some cases, side reactions were observed. When 4-chlorophenyl isocyanate reacted with iminophosphorane 135 (R= Pr ), along with the corresponding pteridin-4(377)-one (43%), the hydrolyzed compound, 3-isopropylpteridine-2,4-(177,377)-dione (26%), was also isolated. In cases with additional functional groups in the pteridine substrate such as esters, polycyclic compounds such as the imidazo[2,T ]pteridine derivative 138 (37%) were obtained. Similarly, Wallyl and W(l-methylprop-2-enyl) groups in 137 gave imidazo[2,l- ]pteridines 139 by iodoamination. 

In heterocyclic chemistry it can be misleading to speak of covalent addition to mean both a product of an addition reaction, such as the hydration of a neutral substrate (i.e., transformation of pteridine to the 4-hydroxydihydro derivative),20 and a product of an attachment reaction, such as the reaction of the hydroxide ion with the ring carbon of a heteroaromatic cation.21... 

The mode of action of the sulfonamides as antagonists of 4-aminobenzoic acid (PAB) is well documented, as is the effect of physicochemical properties of the sulfonamide molecule, e.g. pK, on potency (B-81MI10802). Sulfonamides compete with PAB in the biosynthesis of folic acid (44), a vital precursor for several coenzymes found in all living cells. Mammalian cells cannot synthesize folic acid (44), and rely on its uptake as an essential vitamin. However, bacteria depend on its synthesis from pteridine precursors, hence the selective toxicity of sulfonamides for bacterial cells. Sulfonamides may compete with PAB at an enzyme site during the assembly of folic acid (44) or they may deplete the pteridine supply of the cell by forming covalently-bonded species such as (45) or they may replace PAB as an enzyme substrate to generate coupled products such as (46) which are useless to the cell. 

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