Nucleosides functions

Our studies showed that i) substitution of an exocyclic amino group of dG is effective in modulating the chemical properties of dG toward one-electron oxidation, and ii) decomposition of the guanine radical cation was effectively suppressed near dphG. These results indicate that dphG is a prototype of nucleosides functioning as an intrinsic antioxidant of duplex DNA toward one-electron oxidation. 

Scheme 13 Example nucleoside-functionalized, delocalizable radicals.

The early attempts to use relatively easily available diastereomerically pure nucleoside 3 -0-(2-cyanoethyl-AT,AT-diisopropylphosphoramidite) monomers for the stereospecific synthesis of PS-Oligos failed because of inevitable racemiza-tion of Pm intermediate caused by an excess of lff-tetrazole necessary for efficient elongation of oligonucleotide chain [13]. An idea to use for that purpose appropriately protected nucleosides functionalized at 3 -0 position with 2-thio-1,3,2-oxathiaphospholane moiety arose from the studies on the reactions of di-substituted phosphorothioates with oxiranes [14,15], and in particular from the observation that PS-PO exchange in 0,0-diphenyl phosphorothioate (8) upon treatment with ethylene oxide in methanol solution resulted in formation of... 

The directed protection of nucleoside functional groups is a fundamental problem in nucleoside and nucleotide chemistry. Although several chemical methods are available for the regioselective acylation of the nucleoside carbohydrates, enzymatic... 

After DMTr protection of the 5 -OH nucleoside function, the TBDMS group was introduced at the 2 -OH position as previously described, >l2 and the expected phosphoramidite synthons were obtained using standard procedures. l Preparation of the derivatized solid supports (long-chain alkylamine on controlled-pore glass beads (LCA-CPG)) was achieved as usual, 2 with the loaded yields ranging from 18 to 26 /tmol g l. 

Caton-Williams et al7 reported a one-pot synthesis of nucleoside 5 -(a-P-thio) triphosphates (89) and phosphorothioate nucleic acids without protecting any nucleoside functionalities. The chemistry of this faeile synthesis involves the treatment of unprotected nucleosides with a mild phosphitylating reagent (salicyl phosphorochloridite and pyrophosphate) followed by sulfurization and hydrolysis to afford the corresponding analogues. These compounds can be easily purified by ion-exchange chromatography. 

The fundamental problem of oligodeoxyribonucleotide synthesis is the efficient formation of the intemucleotidic phosphodiester bond specifically between C-3 and C-5 positions of two adjacent nucleosides. Any functional group (NH of nucleic base the other OH of deoxy-... 

Adenosine, 6-amino-9-P-ribofuranosyl-9-ff-purine (see Table 1), is an endogenous nucleoside found in all ceUs of the body. Its ubiquitousness suggests that adenosine functions as an autocoid and that its actions are mediated by specific receptors on the plasma membranes of all ceUs. 

CH2(OMe)2, CH2 = CHCH2SiMe3, MeaSiOTf, P2O5, 93-99% yield." This method was used to protect the 2 -OH of ribonucleosides and deoxyribo-nucleosides as well as the hydroxyl groups of several other carbohydrates bearing functionality such as esters, amides, and acetonides. 

Decitabine (5-aza-deoxycytosine) is an analog of the nucleoside 2 -deoxycytidine. It is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and by inhibition of the enzyme DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. DNA hypomethylation is achieved at concentrations below those required to significantly inhibit DNA synthesis, which may promote restoration of function to genes associated with control of cellular differentiation and proliferation. Cytotoxicity in rapidly dividing cells may also result from covalent adducts between DNA methyltransferase and decitabine. 

This approach offers unique opportunities for the generation of multi-functionalized cyclic 2-azadiene systems. A wide variation of the substitution pattern at the positions N-1 and C-6 can be determined by an appropriate choice of the aldehyde and amine. Various substituents can easily be introduced at the C-3 position via addition/elimination reactions on the sensitive imidoyl chloride moiety [24]. Upon reaction with bi-functional reagent, an adequately AT-protected 2(lH)-pyrazinone was elaborated into C-nucleoside analogues (Scheme 8). The desired skeleton and functionalities were obtained by oxidation-cyclization reaction followed by photochemical removal of the protective o-nitrobenzyl group [25]. 

The high chemoselectivity for the Baeyer-Villiger process was utilized in the synthetic elaboration of another hetero-bicyclic substrate. The biooxidation only provides the expected unsaturated lactone in a desymmetrization reaction without compromising the olefin functionality. The biotransformation product was then converted to pivotal intermediates for C-nucleosides like showdomycin, tetrahydro-furan natural products like kumausyne, and goniofufurone analogs in subsequent chemical operations (Scheme 9.17) [161]. 

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)... 

Removal of the 5 -hydroxyl group of748 (FTAC) or other related nucleosides, or substitution by another functional group, is interesting from the... 

Nucleoside triphosphates have high group transfer potential and participate in covalent bond syntheses. The cyclic phosphodiesters cAMP and cGMP function as intracellular second messengers. 

Adenosine deaminase deficiency is associated with an immunodeficiency disease in which both thymus-derived lymphocytes (T cells) and bone marrow-derived lymphocytes (B cells) are sparse and dysfunctional. Purine nucleoside phosphorylase deficiency is associated with a severe deficiency of T cells but apparently normal B cell function. Immune dysfunctions appear to result from accumulation of dGTP and dATP, which inhibit ribonucleotide reductase and thereby deplete cells of DNA precursors. 

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