Nucleoside carboxylates

Carbonyl (C 0) nucleobase/nucleoside Carboxyl (C-0,0-H) amino acid i Carboxylate (COO ) amino acid O Phenol (ArOH) amino acid Carboxamide (NC=0) peptide Hydroxyl (0-H) monosac aride... 

In a final example of NMR-alded biochemical Interpretation I wish to comment on the enzymatic activity of nucleoside carboxylates of the type I-III ... 

Amino acids, nucleosides, carboxylic and sulphonic acids Reversed phase [116]... 

Acetylation of hydroxyl groups and esterification of carboxyl groups have been observed ia a limited number of cases but, ia geaeral, have ao preparative advantage over chemical methods. By comparison, phosphorylation has been useful ia the preparatioa of modified purine and pyrimidine mononucleotides from their corresponding nucleosides, eg, 6-thioguanosiae [85-31-4] (51) (97). 

Attention has been drawn to the potential of phosphoric acid anhydrides of nucleoside 5 -carboxylic acids (14) as specific reagents for investigating the binding sites of enzymes. For example, (14 B = adenosine) inactivates adenylosuccinate lyase from E. coli almost completely, but has little effect on rabbit muscle AMP deaminase. The rate of hydrolysis of (14) is considerably faster than that of acetyl phosphate, suggesting intramolecular assistance by the 3 -hydroxyl group or the 3-nitrogen atom. 

Hypermodified nucleosides that contain an attached amino acid at C(6) are important in the biochemistry of RNAs. The Ni11 complex with N-[(9-/3-D-ribofuranozylpurin-6-yl)-carbamoyl]-threonine (699) forms a very stable complex involving N(l) of the purine ring, the amide-N and the carboxylate of the attached threonine as donors.1837... 

The thioester hypothesis can be summed up as follows the formation of thiols was possible, for example, in volcanic environments (either above ground or submarine). Carboxylic acids and their derivatives were either formed in abiotic syntheses or arrived on Earth from outer space. The carboxylic acids reacted under favourable conditions with thiols (i.e., Fe redox processes due to the sun s influence, at optimal temperatures and pH values) to give energy-rich thioesters, from which polymers were formed these in turn (in part) formed membranes. Some of the thioesters then reacted with inorganic phosphate (Pi) to give diphosphate (PPi). Transphosphorylations led to various phosphate esters. AMP and other nucleoside monophosphates reacted with diphosphate to give the nucleoside triphosphates, and thus the RNA world (de Duve, 1998). In contrast to Gilbert s RNA world, the de Duve model represents an RNA world which was either supported by the thioester world, or even only made possible by it. 

Methyl oxetane-2-carboxylate derivatives (e.g., 284), obtained by ring contraction of aldonolactones, have been employed for the synthesis (279) of the nucleoside / -noroxetanocin [9-(/ -D-eryt/iro-oxetanosyl)adenine, 304] and its a-anomer via an a-chloride obtained by a modified Hunsdiecker reaction. Displacement of chloride by adenine and debenzylation gave 304. The threo isomer of304, /J-epinoroxetanocin (305), was likewise synthesized from D-lyxono-1,4-lactone. The oxetane nucleosides display potent antiviral activity against the human immunodeficiency virus (HIV). 

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

The design of fluorescent sensors is of major importance because of the high demand in analytical chemistry, clinical biochemistry, medicine, the environment, etc. Numerous chemical and biochemical analytes can be detected by fluorescence methods cations (H+, Li+, Na+, K+, Ca2+, Mg2+, Zn2+, Pb2+, Al3+, Cd2+, etc.), anions (halide ions, citrates, carboxylates, phosphates, ATP, etc.), neutral molecules (sugars, e.g. glucose, etc.) and gases (O2, CO2, NO, etc.). There is already a wide choice of fluorescent molecular sensors for particular applications and many of them are commercially available. However, there is still a need for sensors with improved selectivity and minimum perturbation of the microenvironment to be probed. Moreover, there is the potential for progress in the development of fluorescent sensors for biochemical analytes (amino acids, coenzymes, carbohydrates, nucleosides, nucleotides, etc.). 

A more complex pathway of activation is seen in N-amino acid derivative of phosphoramidic acid diesters of antiviral nucleosides, as exemplified by prodrugs of stavudine (9.79, Fig. 9.14) [153 -155], The activation begins with a carboxylesterase-mediated hydrolysis of the terminal carboxylate. This is followed by a spontaneous nucleophilic cyclization-elimination, which forms a mixed-anhydride pentacycle (9.80, Fig. 9.14). The latter hydrolyzes spontaneously and rapidly to the corresponding phosphoramidic acid monoester (9.81, Fig. 9.14), which can then be processed by phosphodiesterase to the nucleoside 5 -monophosphate, and by possible further hydrolysis to the nucleoside. 

A series of C-nucleoside analogs of type 1.5 were prepared from the reaction of 1-bromodeoxyheptulose derivatives with 3-arylamino-2-cyano-3-mercaptoacrylic acid ethyl ester, 3-amino-5-thioxopyrazolin-4-carboxylic acid ethyl ester, and 2-amino-4-thioxo-4,5-dihydro-l//-benzo[b][l,4]-diazepin-3-carboxylic acid ethyl ester (86PHA548). 

From 133-tiiazines 23 and 5-amino-4-imidazole-carboxylic acids 24 a variety of purines and purine nucleosides 25 have been prepared via an inverse electron demand Diels-Alder reaction <99JA5833>. 

Imidazo[4,5- ]pyridines can be synthesized by a large number of routes, from which condensation of the appropriate carboxylic acid or acid chloride with the corresponding diaminopyridine, sometimes requiring cyclization of the intermediate amide with strong acid, appears to be the most widely used method <1996CHEC-II(7)283>. A recent example has been reported for the synthesis of pyridoimidazole C-nucleosides, and although the yield in this particular case was low, no epimerization at the C-1 stereocenter was observed (Equation 29) <2003TL5807>. 

These enzymes are systematically named nucleoside 5 -(o -D-glycopyranosyl pyrophosphate) NAD oxidoreductases (E.C. 1.1.1 group). It should be noted that only a few enzymes are known, except for the ones just mentioned, that catalyze oxidation of a primary carbon atom to a carboxylic acid group. 

---