Pyrimidine transformation pathways

The other major class of antimalarials are the folate synthesis antagonists. There is a considerable difference in the drug sensitivity and affinity of dihydrofolate reductase enzyme (DHFR) between humans and the Plasmodium parasite. The parasite can therefore be eliminated successfully without excessive toxic effects to the human host. DHFR inhibitors block the reaction that transforms deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) at the end of the pyrimidine-synthetic pathway. This reaction, a methylation, requires N °-methylene-tetrahydrofolate as a carbon carrier, which is oxidized to dihydrofolate. If the dihydrofolate cannot then be reduced back to tetrahydrofolate (THF), this essential step in DNA synthesis will come to a standstill. 

Takahashi et al. [6] revealed that in Pseudomonas putida (= P. striata) BFO 12996 d-hydantoinase is identical with dihydropyrirnidinase (EC 3.5.2.2), which catalyzes the cyclic ureide-hydrolyzing step of the reductive degradation of pyrimidine bases (Fig. 4). The same results were obtained for other hydantoinases from Pseudomonas sp. [22,23], Com-amonas sp. [23], Bacillus sp. [9], Arthrobacter sp. [24], Agrobacterium sp. [22], and rat liver [25]. From these results, it is proposed that D-amino acid production from dl-5-monosubstituted hydantoins involves the action of the series of enzymes involved in the pyrimidine degradation pathway [24,26,27], However, this contenticm has remained moot because of a lack of systematic studies on the enzymes involved in these transformations [28]. 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

Synthesis of [1,2,3]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-c]pyrimidines A novel approach to [l,2,3]triazolo[l,5-c]pyrimidines is shown in Scheme 55. Batori and Messmer - in the course of their investigations on fused azolium salts - described a synthetic pathway to l,3-disubstituted[l,2,3]triazolo[l,5-c]-pyrimidinium salts <1994JHC1041>. The cyclization was accomplished by transformation of the hydrazone 436. This compound was subjected to an oxidative ring closure by 2,4,4,6-tetrabromo-2,5-cyclohexadienone to give the bicyclic quaternary salt 437 in acceptable yield. 

It is important to note that besides these synthetic pathways a very important access to [ 1,2,4]triazolo[ 1,5 z] pyrimidine derivatives is the Dimroth rearrangement of [l,2,4]triazolo[4,3-c]pyrimidine compounds. This type of ring transformation is specifically discussed in Section 11.16.5.2 these possibilities are also reviewed in Section 11.16.7. As these isomerizations always take place into the direction of the [l,2,4]triazolo[l,5-c]pyrimidine ring, in several studies only these products are described without special (or any) note of the primarily formed [l,2,4]triazolo[4,3-c]pyrim-idine ring. Table 17 contains the stmctures of some [l,2,4]triazolopyrimidines and benzologues with a fusion site of the triazole ring that have been formed via transformation of the isomeric [ 1,2,4] triazolo[4,3-f]-pyrimidine compounds with or without isolation of these intermediates. 

The most important route is the conversion of pyrimidines into 1,3,5-triazines. The first one-step transformation was effected by Taylor and Jefford (62JA3744) by heating the pyrimidine (179) with benzenesulfonyl chloride in pyridine (equation 106). The reaction may be considered as an example of an abnormal Beckmann rearrangement. The mechanism of the reaction of the 4-aminopyrimidine (180) is probably dependent on the nature of the 2-substituent (180, R). If R is an electron-releasing moiety, pathway B seems more likely (Scheme 109). The 4-hydroxypyrimidine (179 R = OH) behaves similarly. Many 2-cyano-1,3,5-triazines may be synthesized by this method. 

The proposed reaction pathway for the electrochemical reduction of 4-aminopyrimi-dine is rather complex and the reader is referred to the original publication Photochemical transformations were carried out to determine whether the 4-amino-pyrimidine wave I reduction product is susceptible to photochemical oxidation, as in the case of other pyrimidine derivatives The resulting data are summarized... 

The present information on the riboflavin biosynthetic pathway is summarized in Figure 1. Briefly, the pathway starts from GTP (1), which is converted into the first committed intermediate 2 by the hydrolytic release of pyrophosphate and of C-8 of the imidazole ring that are both catalyzed by a single enzyme, GTP cyclohydrolase II (reaction I). In Archaea and in fungi, that compound is transformed into 5-amino-6-ribitylamino-2,4(li/,3f/)-pyrimidinedione phosphate (5) by a reduction (reaction IV) that transforms the ribosyl side chain into the ribityl side chain (4) and by subsequent deamination (reaction V) of the pyrimidine ring yielding compound 5. In plants and in eubacteria (reactions II and III), these reaction steps occur in inverse order via the ribosylaminopyrimidine derivative 3. 

The biosynthesis of the deazaflavin chromophore, 5-deaza-7,8-desmethyl-8-hydroxyriboflavin (45) branches off the riboflavin pathway at the level of 5-amino-6-ribitylamino-2,4(lii/,3ii/)-pyrimidinedione (6) as initially suggested on the basis of incorporation studies that also suggested that the benzenoid ring is a shikimate derivative. This was later confirmed by in vivo studies with isotope-labeled 6 and 4-hydroxyphenylpynivate (39). These studies afforded the hypothetical mechanism shown in Figure 25. Dehydrogenation is believed to transform the pyrimidine precursor 6 into the quinoid species 40 that is then nucleophilically attacked by the enolate of... 

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