Thymidine derivatives

Whereas imidazolides of nucleotides react only in organic solvents with phosphates or pyrophosphates to give the corresponding anhydride derivatives in high yield, ATP can also be formed enzymatically in aqueous solution from AMP-Im with inorganic pyrophosphate in the presence of valyl-f-RNA synthetase.[66] A variant of this method is the one-pot reaction of a nucleoside with phosphoryltristriazole and tributylammonium pyrophosphate. 671 An a-methylphosphonyl-/ ,y-diphosphate of a thymidine derivative has been synthesized in a similar way t681... 

The animation of thymidine derivatives can also be carried out as a one-pot reaction, in which the ditetrazolide is prepared in situ from the corresponding dichloride and tetrazole.[1963 Similar reactions are described in references [197], [198] and [33a]. 

Allenylcobaloximes, e.g. 26, react with bromotrichloromethane, carbon tetrachloride, trichloroacetonitrile, methyl trichloroacetate and bromoform to afford functionalized terminal alkynes in synthetically useful yields (Scheme 11.10). The nature of the products formed in this transformation points to a y-specific attack of polyhaloethyl radicals to the allenyl group, with either a concerted or a stepwise formation of coba-loxime(II) 27 and the substituted alkyne [62, 63]. Cobalt(II) radical 27 abstracts a bromine atom (from BrCCl3) or a chlorine atom (e.g. from C13CCN), which leads to a regeneration of the chain-carrying radical. It is worth mentioning that the reverse reaction, i.e. the addition of alkyl radicals to stannylmethyl-substituted alkynes, has been applied in the synthesis of, e.g., allenyl-substituted thymidine derivatives [64],... 

It was found that when 5 -0-(4,4 -dimethoxytrityl) uridine or thymidine derivatives reacted with (n-Bu4N)2S208 in CH3CN under mild conditions, the corresponding depro-tected uridine or thymidine nucleosides were obtained in excellent yields (equation 32)"". 

The 5,6-double bond in activated pyrimidines can participate in thermal [4-1-2] cyclization reactions as demonstrated by the 1,3-dipolar cycloaddition reactions of O-protected thymidine derivatives 483 with the nonstabilized azo-methine ylide 484, which is generated from trimethylamine AT-oxide by reaction with EDA <2002SC1977>. 

Oxidative desulfurization can also be used to prepare pyrimidine derivatives as demonstrated by the reaction of thymidine derivatives 598 with fra r-2-phenylsulfonyl-3-phenyloxaziridine (PSO) 599 at room temperature, where the dethiated derivatives 600 were obtained in very good yield <2004TL6729>. 

Synthesis of the thymidine derivative relies on the older two-step insertion of fluorine. Thus, the hydroxyl group in 3 -deoxythymidine benzoate (51-1) is first converted to the mesylate (51-2). Reaction with potassium fluoride in hydrogen fluoride replaces the mesylate by fluorine (51-3). The fact that this reaction, as that above, proceeds with retention of the configuration mles out simple displacement as the mechanism for this transform. The presence of the methyl group at position 5 negates the need for the chlorination step. Saponification then affords the antiviral agent alovudine (51-4) [52]. 

Fig. 10 Thymidine derivatives labeled with the [99mTc(CO)3]+ core and showing binding to TKs...

Thymidine dimers in which the natural phosphodiester linkage has been replaced by a 2,5-disubstituted tetrazole ring have been synthesized and have been incorporated into oligodeoxynucleotides <02HCA2847>. The synthesis of mono- and bis-3-substituted thymidine derivatives with a polycyclic tetrazole linker (l,5-bis(tetrazol-5-yl)-3-oxapentane) has been reported <02TL1901>. a-Methylene tetrazole-based peptidomimetics were synthesized for inhibition studies of HIV protease <02JCS(P1)172>. A catalytic amount of tetrazole was found to be useful in the syntheses of symmetrical P,P -dialkyl partial esters of methylenebisphosphonic acid from the corresponding acid chloride via a facile two-step, one-... 

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

The oxidation of thymine and thymidine derivatives with superoxide ion in dimethyl sulfoxide (DMSO) or DMF gives ring-contracted imidazolones (88CC1171). Oxidation with sodium persulfate gives a mixture of 5-hy-droxymethyluracils and 5-formyluracils, perhaps by thymine cation radicals (86CL1319 88JOC3421) (Scheme 159). 

Oligonucleotide duplexes containing the benzophenone-modified nucleoside (75) have been shown to undergo a reversible photochemical cross-linking reaction. ° The benzophenone is located in the major groove. On photolysis, a new product is formed, which the authors were unable to characterise, but, based on model reactions, the benzophenone modified thymidine derivative (76) is postulated. On heating at 90°C the cross-link is reversed. 

The thymidine derivatives (146) and (147) undergo cleavage of a C-C bond on irradiation. These reactions are typical Norrish Type I processes and provide a route to study C-3 -DNA radicals. Hydrogen abstraction by the radicals yields a 1 1 mixture of the threo and erythro derivatives (148). The reactions from the P-isomers (146) are generally more efficient than from the a-isomer (147). A study of the photochemical reactivity of the deoxyuridine derivative (149) has been reported. This novel compound is an electron-accepting nucleo base. It has been used as a means of cleaving DNA. The photochemical fission occurs specifically at the 5 -G of 5 GG3 sequences. 

The adducts (240) can be prepared by the irradiation of thymidine in the presence of 8-methoxypsoralen. The photocycloaddition of the thymidine derivative (241) results in the formation of six cyclobutane isomers. ... 

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... 

The conformationally-locked 3 -amino thymidine derivative (47) was prepared and incorporated into DNA as a dimer unit, attaching the amino group via a carbamate or phosphoramidate linkage.Both modifications were found to be destabilising towards both RNA and DNA targets. The hybridisation properties of an amino-modified bicyclic thymine nucleotide (48) have been exam-ined. Using alternate T and (48) residues there is an increase in duplex stability with d(A)io, with no pH dependence. When the amino group is acetylated, the duplex stability is decreased. The locked C-nucleoside oxazole derivative (49) has been incorporated into TFOs where it was found to selectively enhance the stability with a C.G base pair. ... 

Synthesis of thymidine derivatives as potential drugs against HIV 01ZOR807. 

Beaucage and co-workers have prepared thymidine derivatives which contain an ethyl linkage inserted into the glycosidic bond and these have been transformed into reagents suitable for DNA synthesis (167a-d), ... 

The automated synthesis of platinated oligonucleotides has been achieved using /f-phosphonate oligonucleotide assembly. The platinated thymidine derivative (182) was synthesised from the corresponding /f-phosphonate derivative of thymidine by deprotonation with potassium hydroxide and then reaction with trans-[(NH3)2PtCl2]. 

For the second reaction, uridine 5-(L-rhamnopyranosyl pyrophosphate) proved to be a somewhat better substrate than the thymidine derivative. The lack of specificity of this reaction raises the question as to which L-rhamnop5Tanosyl nucleotide is the active substrate in vivo. Both uridine 5-(L-rhamnopyranosyl pyrophosphate) and thymidine 5-(L-rhamnopy-ranosyl pyrophosphate) have been isolated from bacteria, but neither has been obtained from higher-plant tissues. The following reaction has, however, been observed to take place in extracts from mung-bean leaves. ... 

Among sugar modified phosphoramidite derivatives prepared this year are 3, 5 -ethano-2 -deoxyribonucleoside derivatives (118), the 4, 6 -methano carbocyclic thymidine derivative (119), a 2 -0-methyl-6,3 -ethanouridine derivative (120), (R)- and (S)-3, 4 -seco-thymidine derivatives, e.g. (121), and arabino derivatives (122). The first three are conformationally rigid nucleoside analogues, and were made in order to prepare oligonucleotide analogues which bind better... 

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