Functionalization of purines

For recent reviews on the transition metal catalyzed functionalization of purines see (a)... 

Pyrrolopyridines can be lithiated at the 2-position, in direct analogy to pyrrole itself. The reaction is sufficiently mild that it has been applied to the functionalization of purine nucleosides, as illustrated by the examples in Scheme 22. ... 

The lac repressor monomer, a chain of 360 amino acids, associates into a functionally active homotetramer. It is the classic member of a large family of bacterial repressors with homologous amino acid sequences. PurR, which functions as the master regulator of purine biosynthesis, is another member of this family. In contrast to the lac repressor, the functional state of PurR is a dimer. The crystal structures of these two members of the Lac I family, in their complexes with DNA fragments, are known. The structure of the tetrameric lac repressor-DNA complex was determined by the group of Mitchell Lewis, University of Pennsylvania, Philadelphia, and the dimeric PurR-DNA complex by the group of Richard Brennan, Oregon Health Sciences University, Portland. 

The examples in the fourth column (Table IX) concern the protonation of purine and adenine and their derivatives while those of the last column mainly reflect Kleinpeter s contributions (Table VIII) to the functional tau-tomerism of 7-hydroxy-l,2,4-triazolo[l,5-a]pyrimidines. 

It would not be too far fetched to state that life on this planet is totally dependent on two compounds based on the purine nucleus. Two of the bases crucial to the function of DNA and flNA—guanine and adenine—are in fact substituted purines. It is thus paradoxical that the lead for the development of medicinal agents based on this nucleus actually came from observations of the biologic activity of plant alkaloids containing that heterocyclic system, rather than from basic biochemistry. 

The cyclization of o-substituted amides 206 was used for the preparation of a series of purine derivatives 207. In this case, the amine behaved as a nucleophile toward the amide function followed by ring closure to the imidazole ring (Scheme 75) [133]. 

Polar functional groups such as alcohols or phenols 11 or trimethylsilanol 4 are transformed by monofunctional silylating reagents Me3SiX 12 into their hpophilic and often volatile trimethylsilyl ethers 13 whereas water is converted into persilyl-ated water (=Me3SiOSiMe3, hexamethyldisiloxane, HMDSO, 7, b.p. 100 °C). The persilylation of phenols and, in particular, catechol (or hydroquinone) systems (Scheme 2.1) protects them efficiently against air oxidation even at temperatures of up to 180 °C. (cf, e.g., the silylation-amination of purine nucleosides with dopamine hydrochloride in Section 4.2.4)... 

Figure 33-2. Tautomerism of the oxo and amino functional groups of purines and pyrimidines.

After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). Special attention is given to acetylcholine, glutamate, GABA, noradrenaline, dopamine, 5-hydroxytryptamine and the peptides but the purines, histamine, steroids and nitric oxide are not forgotten and there is a brief overview of appropriate basic pharmacology. 

Xi H, BL Schneider, L Reitzer (2000) Purine catabolism in Escherichia coli and function of xanthine dehydrogenase in purine salvage J Bacterial 182 5332-5341. 

Point mutations can occur when one base is substituted for another (base substitution). Substitution of another purine for a purine base or of another pyrimidine for pyrimidine is called a transition, while substitutions of purine for pyrimidine or pyrimidine for purine are called transversions. Both types of base substitution have been identified within mutated genes. These changes lead to a codon change which can cause the wrong amino acid to be inserted into the relevant polypeptide and are known as mis-sense mutations. Such polypeptides may have dramatically altered properties if the new amino acid is close to the active center of an enzyme or affects the three-dimensional makeup of an enzyme or a structural protein. These changes, in turn, can lead to change or reduction in function, which can be detected as a change in phenotype of the affected cells. 

STM images of molecules are often a sensitive function of the tunnel conductance. For example, when examining TMPyP on Au( 111 )-I, the iodine underlayer was imaged at a tunnel resistance of 5 X 10 ohms while the electron density of TMPyP was observed at 8 X 10 ohms [484], Similar effects have been noted for protoporphyrins [488] and purines [489,490] adsorbed on graphite. 

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

The synthesis of purine nucleotides (1) starts from IMP. The base it contains, hypoxanthine, is converted in two steps each into adenine or guanine. The nucleoside monophosphates AMP and CMP that are formed are then phos-phorylated by nucleoside phosphate kinases to yield the diphosphates ADP and GDP, and these are finally phosphorylated into the triphosphates ATP and CTP. The nucleoside triphosphates serve as components for RNA, or function as coenzymes (see p. 106). Conversion of the ribonucleotides into deoxyribo-nucleotides occurs at the level of the diphosphates and is catalyzed by nucleoside diphosphate reductase (B). 

I I 3. The answer is c. (Hardman, pp 1243-1247.) Antimetabolites of folic acid such as methotrexate, which is an important cancer chemotherapeutic agent, exert their effect by inhibiting the catalytic activity of the enzyme dihydrofolate reductase. The enzyme functions to keep folic acid in a reduced state. The first step in the reaction is the reduction of folic acid to 7,8-dihydrofolic acid (FH2), which requires the cofactor nicotinamide adenine dinucleotide phosphate (NADPH). The second step is the conversion of FH2 to 5,6,7,8-tetrahydrofolic acid (FH ). This part of the reduction reaction requires nicotinamide adenine dinucleotide (NADH) or NADPH. The reduced forms of folic acid are involved in one-carbon transfer reactions that are required during the synthesis of purines and pyrimidine thymidylate. The affinity of methotrexate for dihydrofolate reductase is much greater than for the substrates of folic acid and FH2. The action of... 

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