2-Amino-6- pteridine

Figure 8. Probe map of E. coli dihydrofolate reductase-methotrexate (10) complex. The calculated minimum energy positions for an ammonium probe (blue) and carboxylate oxygen probe (yellow) closely match the experimental positions for the pteridine amino groups and the carboxyl of methotrexate (20,21). The molecular surface of the enzyme is purple, while all bonds are color-coded by atom type carbon = white, nitrogen = blue, oxygen = red, sulfur = yellow. 

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). 

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. 

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). 

Another important correlation between structure and properties in the pteridine series is seen in the solubilities, to which insufficient attention has been paid in general. Introduction of an amino group into pteridine (1) lowers the solubility in all solvents despite the fact... 

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

The reactivity of the amino groups at the pteridine nucleus depends very much upon their position. All amino groups form part of amidine or guanidine systems and therefore do not behave like benzenoid amino functions which can usually be diazotized. The 4-, 6-and 7-amino groups are in general subject to hydrolysis by acid and alkali, whereas the 2-amino group is more stable under these conditions but is often more susceptible to removal by nitrous acid. 

Aminopteridine is the most sensitive to acid hydrolysis, and 6-amino- and 6-dimethyl-amino-pteridine are also hydrolyzed, even by cold 0.0IN hydrochloric acid, too rapidly for accurate determination of the cation form (52JCS1620). 2-Amino- and 4-amino-pteridine are not readily attacked by IN HCl at 20 °C but at 100 °C the former compound is destroyed and the latter converted into pteridin-4-one (5UCS474). 2,4-Diaminopteridine can be hydrolyzed by refluxing in 6N HCl for 30 minutes to 2-aminopteridin-4-one (pterin 2) and after... 

Various 6- and 7-methyl- and 6,7-dimethyl-pteridines bearing either oxo or amino groups in the 2- and 4-positions can be oxidized to the corresponding carboxylic acids by alkaline potassium permanganate on heating. Various lumazine and pterin mono- and di-carboxylic acids have been prepared in this way (48JA3026, 78CB3790). 

Of the classical Hofmann, Curtius, Lossen and Schmidt degradations, only a rare example of the first is known, hypobromite converting 4,7-diamino-2-phenyl-6-pteridinecar-boxamide (208) into 8-amino-2,3-dihydro-6-phenyl-l//-imidazo[4,5-g]pteridin-2-one (209 equation 64) (63JOC1203). 

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