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A new general synthetic method for the preparation of 6-thiopteridines has been developed. The method involves the addition of thiols to intermediate pyrimidine nitrones formed in situ by the reaction of 4-amino-5-nitrosopyrimidines with pyridinium-activated acetonitriles, acetates, acetophenones, and other methylketones. Ca. forty new pteridines were prepared by this method. The preparation of six new 6-pteridinyl ketones, two new 6- pteridinyl ketone thiosemicarbazones, and two new 6-sulfonylpteridines and their 4-acetamido derivatives is also reported. 4-Acetamido-2- amino-7-phenylpteridine 5-oxide was prepared by the reaction of 2- amino-4,6-diacetamido-5-nitrosopyrimidine with either phenylsulfonyl-acetophenone or phenacylpyridinium bromide. Evidence relating to the structure of the acylated 4-amino-5- nitrosopyrimidines used as intermediates in the aforementioned reactions is presented and discussed. Also included in the dissertation are detailed reviews of the following subjects: Pteridine antimalarials, 6-thiopteridines, 6- pteridinesulfonic acids, 6-pteridinesulfonamides, 6-pteridinyl ketones, and pteridine N-oxides.

The introduction of heteroartoms in the pyrazine portion of the pteridine ring has produced compounds which display antifolate activity. The initial objective of this research program was to develop a convenient synthesis of the 8-oxadihydropteridine ring system and to test the resulting compounds for antifolate activity in suitable biological systems.

In an attempt to prepare 6-anilino and 6-benzylaminopteridines, 2,4,7-triamino-6-methylsulfonyl and 2,4,7-triamino-6-methylsulfinylpteridines were prepared and reacted with a number of benzylamines and aniline. These hard nucleophiles gave amine exchange products with no displacement at the 6 position. Aliphatic amines gave exchange in the 2,4-and 7-positions. The exchange occurring in the 7-position must be occurring by an AE mechanism. This is the first such exchange reported in a ring other than a 1,3-azine. Aniline gave no exchange product except in an acid catalyzed reaction, and then gave exchange in only the 2 and 4-positions. Numerous reactions on related substrates, are reported. Soft nucleophiles, thiophenols, gave displacement on the same substrates in the 6-position only. Three new pteridine 5-oxides were prepared. One of these was prepared by a new synthetic route using an intramolecular cyclization of a 5-nitropyrimidine. The following subjects are reviewed: amine exchanges, displacement of alkylsulfonyl and alkylsulfinyl moieties in azines, and 6-aminopteridines.

Ph.D., Faculty of Science, University of the Witwatersrand, 2011 / This thesis describes the application pteridine chemistry in various aspects of methodology development and natural product synthesis. The introductory chapter sets the scene by describing naturally occurring pteridines, their applications in biological systems, and recent synthetic strategies. Firstly, Sonogashira coupling reactions employing benzenesulfonyloxy-O-pteridine (27) and terminal alkynes to give various 6-substituted pteridines are described. This methodology allowed for the total synthesis of a natural occurring pteridine, Sepiapterin-C (46). Negishi coupling reactions involving benzenesulfonyloxy-O-pteridine (27) and various Znreagents are also reported. This methodology, representing the first Negishi coupling on a pteridine nucleus, allowed for the introduction of both aryl- and heteroaryl- substituents at the 6- position of the pteridine ring. The use of methanesulfonyloxy-O-pteridine (26) as a coupling partner is also described. Selective deprotection and hydrolysis of the formamidine protecting groups to give either the 6- substituted 2,4-diaminopterine or 2-amino-4-oxo-pteridine (pterin), is described. The synthesized structures are supported by NMR and mass spectral data and melting points where applicable. Novel compounds are verified by NMR spectroscopy, infrared and mass spectrometry.

Several new pterins have been discovered in halophilic and thermoacidophilic archaebacteria. Two of these were identified in the extreme halophiles and were thus called halopterins. One of these halopterins is produced by Halobacterium salinarium, Halobacterium halobium, and Halococcus morrhuae and is called phosphohalopterin-1. It was given this name because it was the first halopterin discovered and it has four monophosphate esters per dimeric pterin. The proposed structure of phosphohalopterin-1 is as follows. [see document for diagram of chemical structure] The other halopterin, which is produced by Halobacterium marismortui, Halobacterium volcanii, and Halobacterial strain GN-1, is called sulfohalopterin-2 because it has two sulfate esters per dimeric pterin and it was isolated and recognized after the isolation of phosphohalopterin-1. The proposed structure of sulfohalopterin-2 is as follows. [see document for diagram of chemical structure] As shown above, both pterins are dimers with an ether linkage connecting the polyol side chains. Both of the halopterins are negatively charged because of the phosphate and sulfate esters on the side chains. In addition to the halopterins, a positively charged pterin has been isolated from Sulfolobus solfataricus. This pterin is very special since no positively charged unconjugated pterin had ever been found in nature before. This pterin is named solfapterin after the species name of the bacteria from which it was obtained. The structure of this pterin is still unknown but the preliminary data indicate that it is an unconjugated pterin with a polyol containing an amine on the side chain. Another positively charged pterin which is different from solfapterin was found in Thermoplasma. All of the above pterins are different from any previously described pterins and thus represent new pterins in the archaebacterial kingdom. The discovery of these new pterins is important both to pterin biochemistry and to archaebacterial taxonomy. These discoveries also open up a new field, that is, the exploration of the function of these new pterins in norunethanogenic archaebacteria. / Ph. D.

Utilization of cyanide as the sole nitrogen source by Pseudomonas fluorescens NCIMB 11764 (Pf11764) occurs via oxidative conversion to carbon dioxide and ammonia, the latter satisfying the nitrogen requirement. Substrate attack is initiated oxygenolytically by an enzyme referred to as cyanide oxygenase (CNO), which exhibits properties of a pterin-dependent hydroxylase. The pterin requirement for Pf11764 CNO was satisfied by supplying either the fully (tetrahydro) or partially (dihydro) reduced forms of various pterin compounds at catalytic concentrations (0.5 µM). These compounds included, for example, biopterin, monapterin and neopterin, all of which were also identified in cell extracts. A related CNO-mediated mechanism of cyanide utilization was identified in cyanide-degrading P. putida BCN3. This conclusion was based on (i) the recovery of CO2 and NH3 as enzymatic reaction products, (ii) the dependency of substrate conversion on both O2 and NADH, and (iiii) utilization of cyanide, O2 and NADH in a 1:1:1 reaction stoichiometry. In contrast to findings reported for Pf11764, it was not possible to demonstrate a need for exogenously added pterin as a cofactor for the PpBCN3 enzyme system. However, results which showed that cells of PpBCN3 contained approximately seven times the amount of pterin as Pf11764 (of which a significant portion was protein-bound) were interpreted as indicating that sufficient bound CNO-cofactor exists, thus eliminating any need for a supplemental source.

The biological activities of some homeosterically related analogs of dihydrofolic acid have been examined involving pyrimido[4,5-b][l,4]oxazine (8-oxapteridine) derivatives. It is anticipated that these compounds might interfere with the essential intermediary metabolic functions of the vitamin and thus serve as potential chemotherapeutic agents. Preliminary toxicity studies in microbial assay systems were disappointing; however, inhibitory effects were demonstrated in cell free enzyme systems. A comparison of the structure/activity relationships was determined using two folic acid coenzyme systems, dihydrofolate reductase and thymidylate synthetase. The 2-amino-4-hydroxy-6-(substituted)-8-oxapteridines were generally more effective inhibitors than the corresponding 2,4-diamino analogs. The relative biological activity of a series of 2-amino-4-hydroxy-6-ω-phenylalkyl derivatives were examined, and the most active derivative was the 6-phenylethyl analog which appears to function as a mixed-type inhibitor involving partially competitive and partially non-competitive inhibition.

Diss. (sammanfattning)--Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.