Purine nucleotides analogues

Bis(hydroxymethyl)phosphonic acid esters that incorporated thymine were employed as a backbone to prepare short oligonucleotide chains. This chain was prepared by condensation of the bis(4,4 -dimethoxytrityl) protected phosphonic acid and iV or N -(2-hydroxyethyl)thymine in the presence of l-(2-mesitylenesul-fonyl)-3-nitro-l,2,4-triazole or by an Appel reaction with or N -(2-aminoethyl)thymine (89a-h). Selective removal of one DMT-group and phos-phitylation yielded the building blocks for solid supported synthesis of the short oligomers by the phosphoramidite approach. Holy has reported the synthesis of 8-amino and 8-substituted amino derivatives of acyclic purine nucleotide analogues. The 8-amino, 8-methylamino- and 8-dimethylamino-adenine and -guanine analogues of iV-(2-phosphonomethoxyethyl) and (S)-iV-(3-hydroxy-2-phosphono-methoxy-propyl) derivatives of purines (90a-i), were prepared by... 

A number of purine nucleotide analogues can mimic the effects of natural purine ribonucleotides on PP-ribose-P amidotransferase and thereby effect feedback inhibition of the entire pathway (69, 60). Such nucleotide analogues may be synthesized by cells from purine bases or nucleosides presented to them. A number of compounds with potent inhibitory properties, such as 6-mercaptopurine, 6-thioguanine, and 6-methylmercaptopurine ribonucleoside, inhibit purine biosynthesis de novo in this way, although it is not known whether this action is responsible for the growth inhibition. 

The acyclic nucleoside phosphonates (ANPs) can be considered as nucleotide rather than nucleoside analogues, in that, besides the purine or pyrimidine base, they contain an (acyclic) sugar moiety to which a phosphonate is attached. In these nucleotide analogues (Fig. 2), the phosphoric ester grouping (= P-O---C-----) is... 

Since one of the catalytic actions of reverse transcriptase is DNA synthesis, analogues of pyrimidine and purine nucleotides inhibit this process. A drug, zidovudine, azi-... 

Reagents A Convenient Route to sec- and tert- 6-Alkylpurines. Tetrahedron Lett. 1996, 37, 1285-1288. (c) Dvorakova, H. Dvorak, D. Holy, A. Synthesis of Acyclic Nucleotide Analogues Derived from 6-(sec- or tert-Alkyl) purines via Coupling of 6-Chloropurine Derivatives with Organocuprates. Collect. Czech. Chem. Commun. 1998, 63, 2065-2074. (d) Hocek, M. Holy, A. Perfluoroalkylation of 6-Iodopurines by Trimethyl(perfluoro-alkyl)silanes. Synthesis of 6-(Perfluoroalkyl)purine Bases, Nucleosides and Acyclic Nucleotide Analogues. Collect. Czech. Chem. Commun. 1999, 64, 229-241. 

Many 6-alkylaminopurine nucleosides are important adenosine receptor antagonists, and acyclic nucleotide analogues derived from 6-dialkylaminopurines are strong antivirals, anti-neoplastic agents, and immunomodulators. Recently, several 6-(arylalkynyl)-, 6-(arylalkenyl)-, and 6-(arylalkyl)purines have been reported to exhibit cytokinine activity. Suzuki crosscoupling reactions of 9-benzyl-6-chloropurine with boronic acids have recently been reported to provide 6-substituted purines in moderate to excellent yields (Eq. (46)) [77]. 

Methotrexate, a common antimetabolite, was introduced several decades ago for the treatment of psoriasis and remains an effective therapeutic approach. It is a synthetic analogue of folic acid that acts as a competitive inhibitor of the enzyme dihydrofolate reductase, that is responsible for the conversion of dihydrofolate to tetrahydrofolate. Tetrahydrofolate is an essential cofactor for the synthesis of thymidy-late and purine nucleotides required for DNA and RNA synthesis. Methotrexate inhibits replication and function of T and B cells and suppresses secretion of various cytokines such as IL-1, IFN-y,... 

Konigk, E. (1978) Purine nucleotide metabolism in promastigotes of Leishmania tropica inhibitory effect on allopurinol and analogues of purine nucleosides. Tropenmed. Parasitol. 29 435-438. 

Regardless of the physiological role of the purine nucleoside kinases, adenosine kinase is very important in cancer chemotherapy with purine nucleoside analogues. Attempts are being made to treat tumor cells with purine nucleosides in which the base and sugar moieties have been altered from the normal structures. Conversion to nucleotides is necessary for the expression of the pharmacological activity of many of these compounds, and this is accomplished through the broad substrate specificity of adenosine kinase. 

Cell proliferation may be decreased by using various structural analogues to inhibit nucleic acid synthesis. Amethopterin (methotrexate) closely resembles folic acid (page 165) in structure and prevents the formation of the purine precursors of DNA, RNA and ATP. 6-Mercaptopurine is a purine analogue which interferes with the pathway in which the phosphoribosyl precursors of the purine nucleotides are formed. 5-Fluorouracilis a competitive inhibitor of the conversion of uridylic acid (dUMP) into thymidylic acid (dTMP). 

The principle of selection is to place these cells into a selective medium in which the de novo pathway of nucleotide synthesis is inhibited. The key to this is the compound, aminopterin which is an analogue of folic acid and a specific inhibitor of dihydrofolate reductase, an essential enzyme for the formation of tetrahydrofolate (FH4) required as a coenzyme of the de novo purine nucleotide synthesis pathway. Tetrahydrofolate is also required for the formation of thymidine. However, if hypoxanthine and thymidine are provided in the culture media of HGPRT+ cells they will be able to grow normally. On the other hand HGPRT" cells would have no means of synthesizing purine nucleotides and consequently would be unable to grow. 

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