Acyclic nucleotide analogues

Adefovir (Hepsera) [Antiviral/Acyclic Nucleotide Analogue]... 

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]. 

Cidofovir is an acyclic nucleotide analogue of the monophosphate of cytosine. When phosphoiylated by host cellular enzymes, the active compound cidofovir diphosphate has broad activity against the herpes viruses, including CMV, HSV 1 and 2, VZV, Epstein-Barr virus, and the BK polyomavirus. Cidofovir has primarily been used in the treatment of CMV retinitis in patients who have failed treatment with ganciclovir or foscarnet and in acyclovir-resistant herpes simplex infections. More recently, there is also a growing experience with the use of this medication in kidney transplant patients who have BK virus-associated nephropathy [31], although this interest has been dampened by significant toxicity and only modest clinical activity [32]... 

Non-racemic amino alcohols derived from common amino acids have been employed to prepare acyclic nucleotide analogues (35) with controlled absolute stereochemistry, as structural hybrids of PMEA and PMPA, the propyl homologue of PMEA. L-threonine and L-alanine were used as precursors in... 

Unsaturated phosphonates have been prepared as acyclic nucleotide analogues. Reaction of the (Z)-unsaturated guanine derivative (S3) with triethyl phosphite followed by deprotection... 

Murano, T. Yuassa, Y Koboyakawa, H. Yokomatsu, T. Shibuya, S. Synthesis of acyclic nucleotide analogues possessing a difluoromethylene phosphonyl group at the side chain. Tetrahedron 2003, 59, 10223-10230. 

More traditional masking groups have also been used in combination with an internal ester. The acyclic nucleotide analogue based on 2,6-diammopurine has been further modified as its POM (58) and HOP derivatives [112], suggesting that... 

The acidity constants of the twofold protonated acyclic nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine, H (9,SaPMEAf, as well as... 

The L-arabinose derivative 205 provides the starting point for synthesis of the 2-deoxythreose derivative 206, then converted to the acyclic nucleotide analogue 207 (which is twice as active against cytomegalovirus as its (5)-enantiomer). The chiron 208 has been synthesized starting from L-ascorlric acid, while diacetyl-D-rhamnal has been converted to 209 in six steps. The carbohydrate-derived meso epoxide diacetate 210 has been efficiently desymmetrized (to the monoacetate) using... 

Figure 14 Chemical structures of l,N -ethenoadenosine 5 -monophosphate (8-AMP ) and of uridine 5 -0-thiomonophosphate (UMPS ), as well as of the dianion of the acyclic nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA ). To facilitate comparisons between e-AMP and AMP the conventional atom numbering for adenines is adapted, a procedure which is common [171]. The purine-nucleotide e-AMP [11-13] and the pyrimidine-nucleotide UMPS [11,14] are shown in their dominating anti conformation. H-NMR shift measurements have shown [176] that in solution PMEA adopts an orientation which is similar to the anti conformation of AMP this conclusion is in accord with a crystal structure study [177] of the H2(PMEA) zwitterion.

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... 

Appropriately designed prodrugs, for example, phosphonoamidates (Lee et al. 2005), may allow acyclic nucleoside phosphonates such as tenofovir to be specifically targeted at tissues, that is, lymphatic tissue, where the virus (i.e., HIV) replicates. This principle has been recently extended to another nucleotide analogue, GS-9148 (Cmiar et al. 2008) and its phosphonoamidate prodrug, GS-9131 (Ray et al. 2008). 

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 paper on new approaches to the generation of arylphosphinidenes has been published. The stable bis-azide precursor (133) upon photolysis, or vapour phase thermolysis, gave (134), obviously via the phosphinidene (135) the same product was obtained by photolysis of the phosphaketene (136). The reduction of aryldiazonium salts to arenes with triethyl phosphite or triphenylphosphine is shown to proceed by a radical-chain mechanism. The previously described photo-Arbuzov rearrangement of benzyl phosphites has been used to prepare several acyclic phosphonate nucleotide analogues, e.g. (137). ... 

Cidofovir is a synthetic acyclic pyrimidine nucleotide analogue of cytosine (42). It is a phosphorylated nucleotide that is additionally phosphorylated by host cell enzymes to its active intracellular metabolite, cidofovir diphosphate. This reaction occurs without initial virus-dependent phosphorylation by viral nucleoside kinases. It has antiviral effects by interfering with DNA synthesis and inhibiting viral replication. 

Brel reported an efficient synthesis of a series of new purine and pyrimidine nucleotides containing acyclic phosphonate analogues with a triple or double bond (54) in the carbon skeleton. 

Nucleoside Acyclic Phosphates - It is well established that most nucleoside analogues become biologically active as a result of cellular conversion to phosphomonoesters. For this reason there has been increasing interest in the synthesis of nucleoside phosphotriesters and in some cases, i osphodiesters which might act as membrane soluble pro-drugs of the bioactive nucleotides. The diethyl-, dipropyl- and dibutyl-phosphates (1) of 2, 3 -dideoxy-3-deaza-adenosine have been synthesis and shown to possess anti-HIV-1 activity at non-cytotoxic doses. Phosphate triester derivatives of the anti-leukaemic nucleoside nmbi/io-cytidine have... 

De Clercq, Synthesis of some analogues of l-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) which have different types of acyclic structures. Nucleosides Nucleotides 11 447 (1992). 

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