Pteridine analogues

The enamine 141 can be cyclized to the [l,2,4]triazolopyridopyrimidine 142 upon treatment with sodium ethoxide (Scheme 40) <2002M1297>. This fused tricyclic system may also be obtained, like the pteridine analogue (cf. Scheme 38), from the reaction of hydrazonoyl halides and pyridopyrimidines such as 143, and also by treatment of the triazolopyrimidine 144 with dimethylformamide dimethylacetal (DMF-DMA) dimethylacetal and subsequent ring closure <2003MOL333, 2003HAC491> (Scheme 41). Another series of triazolopyridopyrimidines, for example, 146, can be prepared from a hydrazine-substituted pyridopyrimidine 145, in two ways either directly by reaction with an acid chloride, or via a derived hydrazone (Scheme 42) <1996MI585>. 

The detailed fluorescence characterization of pteridine analogues of adenosine nucleosides has been reported <2001ABI231>. The 4-aminopteridin-7-one 8-nucleosides 215 and 216 had absorption maxima at 310 and 330 nm, respectively, and both emit at 430 nm. The fluorescence was monoexponential with a lifetime of 3.8 and 4.3 ns. 

Protonated flavin and pteridine analogues formed in the presence of perchloric acid can also function as efficient photocatalysts for the photooxidation of benzyl alcohols by oxygen via H+-catalyzed photoinduced electron transfer [307-309]. In contrast to the case of flavin and pteridine analogues, the triplet excited state of coenzyme pyrroloquinolinequinone (PQQ) by itself can oxidize benzyl alcohols to the corresponding aldehydes via photoinduced electron transfer, since the oxidizing ability of the triplet excited state of PQQ is much higher than that of flavin and pteridine analogues [310],... 

Triamterene is the primary compound selected from a host. (synthetic pteridine analogues.Although it bears a slruc-aral resemblance to folic acid and certain dihydrofolate re-Juclase inhibitors, it has little, if any. of their activities. ... 

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. 

Another approach uses the reaction of 6-chloro-5-nitropyrimidines with a-phenyl-substituted amidines followed by base-catalyzed cyclization to pteridine 5-oxides, which can be reduced further by sodium dithionite to the heteroaromatic analogues (equation 97) (79JOC1700). Acylation of 6-amino-5-nitropyrimidines with cyanoacetyl chloride yields 6-(2-cyanoacetamino)-5-nitropyrimidines (276), which can be cyclized by base to 5-hydroxypteridine-6,7-diones (27S) or 6-cyano-7-oxo-7,8-dihydropteridine 5-oxides (277), precursors of pteridine-6,7-diones (278 equation 98) (75CC819). 

The general interest in the pteridines is due to their widespread occurrence in both the animal and plant kingdoms, implying potential biological activity and drug-type properties in structural analogues. 

In another study, 4-methylpteridine (6) and 4-trifluoromethyl pteridine (7) showed that substituents can, in some instances, not only change the extent of hydration but also the preferred site of hydration (Figure 5).17 Experimental results indicate that the 4-trifluoromethyl analogue hydrates initially across the 5,6- and 7,8-double bonds to form the dihydrate. Over... 

K., Wachter, H., Werner-Felmayer, G., Mayer, B., Identification of the 4-amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase, Biochem. J. 320 (1996), p. 193-196... 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

Trimethoprim (Trimpex, Proloprim) is a structural analogue of the pteridine portion of dihydrofolic acid. It differs from the sulfonamides in that it acts at a second step in the folic acid synthetic pathway that is, it... 

The one-step synthesis of further tri- and tetracyclic pteridine derivatives from 2-aminopyrazine 153 has also been described <2001JHC1173>. Cyclic analogues of A -[bis(methylthio)methylene]amino reagents such as 2-(methylthio)-2-thiazoline, 5,6-dihydro-2-(methylthio)-4//-l,3-thiazine, 2-(methylthio)-2-imidazoline, 2-(methylthio)-l,4,5,6-tetrahydro-pyrimidine, 2-(methylthio)-2-pyrazine, and 2-chloropyrimidine reacted with aminopyrazine 153 to afford thiazolo/thia-zino[2,3-3]- 159 ( = 1 (53%), n = 2 (42%)), imidazo/pyrimidino[2,l-/ ]- 160 ( = 1 (53%), = 2 (57%)), pyrazino[2,l-/ ]-161 (21%), and pyrimido[2,l-/ ]-pteridine 162 (42%) derivatives, respectively. 

Folate analogues continue to have importance in chemotherapy, especially heterocyclic analogues other than pteridines which are covered in Chapters 10.15-10.17 and 10.19. 1,3-Dimethyllumazine analogues of folates for use as model compounds have been prepared by side-chain elaboration of 6-bromomethyl-l,3-dimethyllumazine (Scheme 34) <1996JHC341>. More notable in this work, however, was the synthesis of the bromomethyl precursor itself in addition to routine bromination of the 6-methyllumazine 175 prepared by condensation of dihydroxyacetone with 5,6-diamino-l,3-dimethyluracil, a cycloaddition reaction between trimethylsilyl enol ethers and the pyrimidyl bisimine 177, via cycloadducts such as 176, afforded substituted pteridines in moderate to good yields. 

Pteridine nucleosides can be synthesized by a variety of methods typical of the field. Thus a pteridine anion formed by deprotonation of 193 with a hindered base (DBU) coupled with an a-halodeoxyribofuranose to afford the corresponding nucleoside 194 with good stereoselectivity, a significant improvement upon previous methods using mercuric salts as promoters (Scheme 38) <1996TL8355>. Riboside analogues were also prepared. 

---