Adenine derivatives

For the investigation of molecular recognition in micelles, adenine derivatives and positively charged (thyminylalkyl)ammonium salts such as shown in Figure 30 were prepared, which were solubilized in sodium dodecyl sulfate (SDS) solutions. Nmr studies have shown that binding occurs in a 1 1 molar ratio in the interior of the micelles as illustrated in Figure 30 (192). 

The utility of the Zincke reaction has been extended to the preparation of various NAD and NADH analogs. Holy and co-workers synthesized a series of NAD analogs containing nucleotide bases as a means to study through-space interaction between the pyridinium and base portions. Nicotinamide-derived Zincke salt 8 was used to link with various adenine derivatives via tethers that contained hydroxyl (105 —> 106, Scheme 8.4.35), phosphonate (107—>108, Scheme 8.4.36), and carboxylate "... 

Occurrence, chemistry, synthesis and cytokinin activity of l -methyl-rran.s-zeatin and its analogs (glycosylated adenine derivatives) 97H(46)659. 

Water-soluble methylglyoxal adenine derivative 11 has recently been reported as a potentiator of wild-type and F508del-CFTR mutations in several cell lines [55]. Ex vivo addition of 11 to cftr mice colonic epithelium induced a dose-dependent elevation of chloride secretion with a measured EC50 of 175 + 1.1 pM. In vivo, in cftr+/ mice, addition of 11 in the presence of isoprenaline induced a dose-dependent salivary secretion with an EC50 of 7.1 + 1.1 pM whereas no effect of isoprenaline and 11 was observed on the salivary secretion of cftr mice. 

Reaction of 6-halopurines with Michael acceptors under Heck conditions gives N- -substituted hypoxanthine derivatives <00CCC797>. Reactions of a series of 1-aminobenzimidazoles and l-amino-3-methylbenzimidazolium chlorides with 2,4-pentanediones afford pyridazino[l,6-a]benzimidazoles and 2-pyrazolylanilines, the product ratio depending on conditions and on the electronic character of the substituents at the benzene moiety <00BMC37>. Cyclization reactions of adenine derivative 75 with different amines or hydrazine afford tricyclic polyaza compounds 76 <00CCC1109>. 

Glutamol adenylate (8) (Table 3) is a competitive inhibitor (A)= 3 pmol 1 ) of GluRS from E. coli The A -benzoyl adenine derivative is also an inhibitor (A) = 60pmolG ). Replacing adenine with other bases (purine, cytosine, dihydrocytosine, uridine) resulted in a more than 1000-fold loss of activity, indicating the importance of the contribution of the adenine ring to enzyme binding. 

The effect of 6-mercaptopurine on the incorporation of a number of C-labelled compounds into soluble purine nucleotides and into RNA and DNA has been studied in leukemia L1210, Ehrlich ascites carcinoma, and solid sarcoma 180. At a level of 6-mercaptopurine that markedly inhibited the incorporation of formate and glycine, the utilization of adenine or 2-aminoadenine was not affected. There was no inhibition of the incorporation of 5(or 4)-aminoimidazole-4(5)-carboxamide (AIC) into adenine derivatives and no marked or consistent inhibition of its incorporation into guanine derivatives. The conversion of AIC to purines in ascites cells was not inhibited at levels of 6-mercaptopurine 8-20 times those that produced 50 per cent or greater inhibition of de novo synthesis [292]. Furthermore, AIC reverses the inhibition of growth of S180 cells (AH/5) in culture by 6-mercaptopurine [293]. These results suggest that in all these systems, in vitro and in vivo, the principal site at which 6-mercaptopurine inhibits nucleic acid biosynthesis is prior to the formation of AIC, and that the interconversion of purine ribonucleotides (see below) is not the primary site of action [292]. Presumably, this early step is the conversion of PRPP to 5-phosphoribosylamine inhibited allosterically by 6-mercaptopurine ribonucleotide (feedback inhibition is not observed in cells that cannot convert 6-mercaptopurine to its ribonucleotide [244]. 

This enzyme [EC 2.4.1.118], also known as UDP-glucose-zeatin 7-glucosyltransferase, catalyzes the reaction of UDP-glucose with an A -alkylaminopurine to produce UDP and an A -alkylaminopurine-V-jS-D-glucoside. The enzyme can act on a number of -substituted adenine derivatives (e.g., zeatin and A -benzylaminopurine). However, it has been reported that A -benzyladenme does not serve as a substrate. Depending on the substrate, a 9-/3-D-glucoside may be the product formed. 

Shea KJ, Spivak DA, Sellergren B. Polymer complements to nucleotide bases. Selective binding of adenine derivatives to imprinted polymers. J Am Chem Soc 1993 115 3368-3369. 

Aldehydo nitriles are readily available and can be used to prepare 4-amino-6-unsubstituted pyrimidines carrying one or more substituents in any of the other positions. Equivalents of the formyl group are also often used, for example, a 3-ethoxy-, 3-amino-, or 3-haloacrylonitrile. Most syntheses with /3-keto nitriles are carried out with equivalents thereof Such equivalents are /3-substituted /3-alkoxy-, /3-amino-, or /3-haloacrylonitriles. /3 -Ester nitrile reactions are also well established. Malononitriles and substituted malononitriles react readily with thiourea and N-substituted thioureas in refluxing ethanolic sodium ethoxide to form pyrimidine-4,6-diamines. An example is the reaction of N2-malononitrile 680 with N2-thiourea 681 to give N4- 4,6-diamino-2-(l//)-pyrimidinethione 682 which was then used in the synthesis of Ns-labeled adenine derivatives <2001JOC5463>. 

Selective oxidation of N-1 of adenine derivatives is typically carried out with peracids <1998JOC3213>, but has also been achieved with hydrogen peroxide and catalytic methyltrioxorhenium (Scheme 10) <2000T10031>. The inclusion of pyridazine-2-carboxylic acid as a stabilizer for reactive rhenium peroxides led to increased yields. Caffeine did not react under these conditions. 

Fluorination of adenine derivatives using elemental fluorine (1% F2 in Fie delivered at a rate of 5-10 j.mol F2 min ) gave the C-8 fluoro analogues in moderate yields <1996JA10408>. Although chloroform was the optimum solvent, this was not suitable for less-soluble, unprotected compounds and ethanol was substituted, although a reduction in yield was observed (Scheme 13). 

FIGURE 9-27 Metabolites produced in Agrobacterium-infected are adenine derivatives. Opines generally are derived from amino acid... 

Table II. Surface Adsorption of Various 14C-Labeled Adenine Derivatives to Beef Brain Lipida...

Adenine derivative Thymine derivative Sodium dodecyl sulfate... 

To test the hypothesis, aliquots of 5.0 mM adenine derivative were mixed with aliquots of 5.0 mM thymine derivative in proportions shown in the table. Each solution also contained 20 mM sodium dodecyl sulfate. The concentration of product measured by nuclear magnetic resonance also is shown in the table. Are the results consistent with formation of a 1 1 complex Explain your answer. 

There are several antitumor antibiotics resembling the synthetic nucleoside antimetabolites discussed on p. 160. They are adenine derivatives with unusual furanose compounds attached to the 9-position. Psicofuranine (54) is an example. The rather more complex example puromycin (55) is also active against trypanosomes and Gram-positive bacteria. Tubercidin (56) and two related antibiotics have an altered purine system. 

Adenine Derivatives. These include (5)-9-(3-hydroxy-2-phosphonyl-methoxypropyl) adenine [(5 )-HlJMl AJ, CyH NjOsl (11), the cychc phosphonate of (S)-HPMPA, (S)-cHPMPA, G Hi2N504P (12). (S)-DHPA, C8H N,02 (13), and adeninylhydroxypropanoic acid alkyl esters [(R,S)-AHPA esters] (14) (Fig. 2). 

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