3 ,5 -cyclic nucleotides

The preparation of (Rp) and (Sp)-N, N, O -tribenzoyladenosine 3, 5 -phosphoranilidates (96) has been greatly improved by treating the cyclic phosphate (97) with oxalyl chloride and a catalytic amount of DMF, rather than the triphenylphosphine-carbon tetrachloride mixture (Appel reaction) used previously, followed by addition of aniline. 5 near-quantitative yield of (97) obtained as a mixture of diastereoisomers is easily separated. The cyclic phosphoramidates (98-100) have also been obtained in improved yield by treating cAMP with a mixture of phosphoryl chloride and trimethyl phosphate (which had previously been pretreated with one-half a molar equivalent of water) at 0°, followed by ammonium carbonate or the appropriate amine. x e (Sp)-diastereoisomers are formed in excess, e.g. for (100) yields of 13 % of the Rp-isomer and 54 % of the Sp-isomer are obtained, and the proportion of Rp-product decreases further if pre-treatment with 

Adenosine 3 -monophosphate is readily cyclized to the 2, 3 -monophosphate by cyanogen bromide in imidazole buffer. 93 It appears that both N-cyanoimidazole and diimidazoleimine are formed, and both reagents can effect the cyclization in aqueous solution, with N-cyanoimidazole being the more effective reagent, particularly in the presence of divalent metal ions (Cu2+, Ni2+, Zn +). They may represent useful alternatives to DCC or carbonylbis(imidazole) in condensation reactions. 

The capacity of the cyclodextrins to induce regioselective cleavage of nucleoside 2, 3 -monophosphates has been explored in a series of papers. a-Cyclodextrin catalyses regioselective P-0(2 ) cleavage of these compounds at pH 

Phosphitylation of 8-bromo-2, 3 -0-isopropylideneadenosine with diethyl phosphorochloridite and triethylamine followed by irradiation of the resultant phosphite triester in acetonitrile affords (111) as a mixture of diastereoisomers which on deprotection gives P/ 5 -anhydroadenosine-8-phosphonic acid. The mechanism proposed involves homolytic fission of the carbon-bromine bond followed by attack on the phosphite by the C-8 radical. 

In RAW264 murine macrophages, Takahashi et al. (2000) identified three cAMP inducible mRNAs, named cI-1, cI-2, and cI-3 (for cAMP inducible genes 1-3. The cI-3 probe was identical to a previously known gene, gly96. 

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FIGURE 11.14 Structures of the cyclic nucleotides cAMP aud cGMP. 

Goldberg, N. D. (1975). Cyclic nucleotides and cell function. In Cell membranes, biochemistry, cell biology, and pathology. edited by G. Weissman and R. Claiborne, pp. 185-202. H. P. Publishing, New York. 

Calmodulin and cyclic nucleotide-dependent second messenger systems... 

Synthesized by soluble guanylyl cyclase and particulate guanylyl cyclase from guanosine triphosphate (GTP). Nitric oxide activates soluble guanylyl cyclase to enhance cyclic GMP production that contributes to various NO actions. Cyclic GMP is hydrolyzed by phosphodiesterases. Cyclic GMP binds to and activates cGMP-dependent protein kinase, phosphodiesterases, and Cyclic Nucleotide-regulated Cation Channels. 

In cyclic nucleotide-regulated channels, this domain serves as a high-affinity binding site for 3-5 cyclic monophosphates. The CNBD of channels has a significant sequence similarity to the CNBD of most other classes of eukaryotic cyclic nucleotide receptors and to the CNBD of the prokaryotic catabolite activator protein (CAP). The primary sequence of CNBDs consists of approximately 120 amino acid residues forming three a-helices (oA-aC) and eight (3-strands ( 31- 38). 

Cyclic Nucleotide-regulated Cation Channels Cyclic Guanosine Monophosphate... 

Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82 769-824... 

Cyclic nucleotides (cAMP and cGMP) are formed enzymatically from the corresponding triphosphates. As ubiquitous second messengers, they mediate many cellular functions which are initiated by first (extracellular) messengers. Their prime targets in eucaryotic cells are protein kinases ( cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase), ion channels and ensymes. 

Adenylyl Cyclases Guanylyl Cyclases Transmembrane Signalling Cyclic Adenosine Monophosphate Cyclic Guanosine Monophosphate Cyclic Nucleotide-gated Channels Phosphodiesterases... 

Hypeipolarisation-activated and cyclic nucleotide-gated-channel. 

Hyperpolarization-activated and Cyclic Nucleotide-gated Channels (HCN)... 

Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes that catalyze the hydrolysis of 3, 5 -cyclic guanosine monophosphate (cGMP) or 3, 5 -cyclic adenosine monophosphate (cAMP) to 5 -guanosine monophosphate (GMP) or 5 -adenosine monophosphate (AMP), respectively. 

Phosphodiesterases. Table 1 Characteristics of the individual Class 1 cyclic nucleotide PDE families... 

PDE1C2 and PDE4A are expressed. PDE1C2 is found in the cilia of the epithelium, where it colocalizes with adenylyl cyclase. PDE4A is found throughout the epithelial layer, but not in cilia. Therefore, as in the kidney mesangial cells, different PDEs must be working on different cyclic nucleotide pools. More recently, substantial data has been developed for compartmenta-tion of cAMP and PDEs in cardiac myocytes. 

Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases molecular regulation to clinical use. Pharmacol Rev 58 488-520... 

Beavo JA (1995) Cyclic nucleotide phosphodiesterases functional implications of multiple isoforms. Physiol Rev 75 725-748... 

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