3 -Amino-3 -deoxythymidine

A. Mononucleotides.—A new journal has appeared in the past year consisting of abstracts of papers published in the nucleotide and nucleic acid fields. The use of nucleosides and nucleotides as potential therapeutic agents has been reviewed. Nucleotides which have been prepared recently using conventional methods of phosphorylation include those derived from 6-methylthiopurine ribonucleoside (la), 5-methylsulphonyluridine (lb), l-(jS-D-ribofuranosyl)-2-pyrimidone (Ic), 3-(jS-D-ribofuranosyl)-4-pyrimidone (Id), and various thionucleosides. - O-Phosphorylated 3 -amino-3 -deoxythymidine (2a) and 5 -amino-5 -deoxythymidine (2b)... 

Amino-5 -deoxythymidine, A-353 5 -Amino-3, 5 -dideoxyadenosine, A-362 5 -Amino-2, 5 -dideoxyuridine 5 -N-Ac, A-419 5 -Amino-3, 5 -dideoxyuridine teri-Butyldimethylsilyl ether, A-420 5 -Amino-2, 5 -dideoxyuridine, A-419 5 -Amino-3, 5 -dideoxyuridine, A-420... 

The V-phosphonoacetyl derivative 85 has been prepared as an analogue of 5-iodo-deoxyuridine -5 -diphosphate,121 and 5 -amino-5 -deoxythymidine has been linked via an amide bond to D- and L-cysteine and D- and L-penicillamine.l22... 

Novel nitrogen-containing intemucleotidic links have been reported. 3 -Amino-3 -deoxythymidine and 5 -amino-5 -deoxythymidine have been linked as the cyanoguanidine 90,125 and the V-methylhydroxylamino-linked dithymidine 91 was made by joining a 5 -aldehyde... 

Carbamoylating activity of all compounds is compared to BCNU for 3 -CTNU, 78% of 5 -amino-5 -deoxythymidine was present as products other than unreacted 5 -amino-5 -deoxythymidine. Three determinations were made for each compound with the standard deviation less than 10% of the mean in all cases. 

Carbocyclic analogues of 5 -amino-5 -deoxy- and 3 -aminos -deoxythymidine have been prepared from previously known cyclo-... 

The addition of lithium azide to ferr-butyldimethylsilyloxy-2-penten-4-olides during the synthesis of a 3 -azido-3 -deoxythymidine derivative66 and the diastereoselective addition of benzy-lamine to (R)-4-0-benzyl-4-hydroxy-2-penten-5-olide giving substituted /9-amino acid derivatives67 have also been reported. 

Quinolones have been shown to act as gyrase inhibitors, and are clinically used as antibiotics. A series of quinolones has been conjugated to the 5 -end of short ODNs as 5 -acylamido derivatives using S -amino-S -deoxythymidine. The presence of the quinolone at the 5 -terminus was shown to greatly enhance... 

However, equivalent potency of enzyme inhibition has been reported for the triphosphates of 3 -deoxythymidine and 3 -amino-3 -deoxythymidine despite the weak antiviral activity of the parent nucleosides (163) and (90) in vitro, both of which are poor substrates for phosphorylation [213, 214]. These observations suggest that the antiviral aetivity of 2, 3 -dideoxynucleo-sides may depend less on the relative inhibitory activities of the triphosphates against isolated RT, but rather reflects the affinity of the parent nucleosides for the cellular kinase enzymes effecting triphosphorylation. Nevertheless, other studies of RT inhibition by nucleoside triphosphates have demonstrated a defined SAR for modifications at the 3 -position [215], and it is likely that the azido substituent of AZT contributes both to the requisite substrate activity for the cellular phosphorylating enzymes, and the specificity of RT inhibition following conversion to the triphosphate. 

Triethylamine tris(hydrofluoride) in the presence of DBU reacts quantitatively with 13. Contrary to all examples so far presented of 1,3,2-oxathiaphos-pholane ring opening condensations, an attack of fluoride ion on phosphorus is not stereospecific when performed with diastereomerically pure species, the mixture of diastereomeric compounds 68 is always produced [93, 94]. Oxathi-aphospholane derivatives of 3 -amino-3 -deoxythymidine 48 and 50 under treatment with triethylamine tris(hydrofluoride) in the presence of DBU, followed by detritylation with acidic ion-exchange resin, provided 3 -deoxythymi-dine-3 -N-phosphoramidofluoridate (69) and 3 -deoxythymidine-3 -N-phos-phoramidofluoridothioate (70) (Scheme 18), further purified by preparative TLC in ca. 80% yield [75]. 

Wang reported the synthesis of dinucleosides, dinucleotides and oligodeoxynucleotides containing 3 -amino-3 -deoxy-3 -N,5 -(i )-C-ethylenethymidine. The bicyclothymidine was prepared from 3 -azido-3 -deoxythymidine and condensed with 5 -0-(H-phosphonyl)thymidine in the presence of triethylamine and 5 -0-(p-nitrophenoxycarbonyl)thymidine derivatives... 

Folate (foUc acid) is an essential vitamin which, in its active form of tetrahydrofolate (THF, Figure 4-1), transfers 1-carbon groups to intermediates in metaboUsm. Folate plays an important role in DNA synthesis. It is required for the de novo synthesis of purines and for the conversion of deoxyuridine 5-monophosphate (dUMP) to deoxythymidine 5 -monophosphate (dTMP). Additionally, folate derivatives participate in the biosynthesis of choline, serine, glycine, and methionine. However, in situations of folate deficiency, symptoms are not observed from the lack of these products as adequate levels of chohne and amino acids are obtained from the diet. (See also Case 3.)... 

Solid-state NMR has been used extensively for characterizing the structures of N-desmethylnefopam HC1 (38), patellin (39), erythromycin A dihydrate (40), and the amorphous nature of ursodeoxycholic acid (41). The conformations of 3 -amino-3 -deoxythymidine (42), gramicidin A (43), and amiodarone HC1 (44) have been confirmed by solid-state NMR. 

The one-carbon groups carried by FH4 are used for many biosynthetic reactions. For example, one-carbon units are transferred to the pyrimidine base of deoxyuridine monophosphate (dUMP) to form deoxythymidine monophosphate (dTMP), to the amino acid glycine to form serine, to precursors of the purine bases to produce carbons C2 and C8 of the purine ring, and to vitamin B12. 

In the area of 5 -di- and tri-phosphates, ATP, GTP, UTP and CTP, with deuterium in all of the 3 -, 4 -, and 5 -positions, have been made enzymically from the labelled ribose (Chapter 2) whilst chemical routes to the 5 -triphosphates of 4-thiouridine, 2-thiocytidine, 5-bromocytidine and [6- N]-adenosine have been described. Azidonucleosides can be converted by treatment with a polystyryl diphenylphosphine into polymer-bound phosphine imines (Vol. 28, p. 272) it has now been reported that the nucleoside phosphine imine can be converted to its 5 -triphosphate before hydrolysis to give the amine. The method was used to convert AZT into the 5 -triphosphate of 3 -amino-3 -deoxythymidine, amongst other cases.A method previously used to make the P -methyl-... 

AZT was used as a precursor to prepare a compound in which fluorescein was linked to the amino group of 3 -amino-3 -deoxythymidine through a thioamide, a link resistant to enzymic degradation, and a spacer. The product was converted to its 5 -triphosphate for use as a chain terminator for DNA dye-terminator sequencing. 3 -Amino-3 -deoxythymidine has been joined in hybrid structures. 

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