Aryl H-phosphonates. 10. Synthesis of nucleoside phosphoramidate and nucleoside phosphoramidothioate analogues via H-phosphonamidate intermediates

Kers, Inger; Stawiński, Jacek; Kraszewski, Adam

doi:10.1016/s0040-4020(99)00656-0

Cited by 23 publications

(29 citation statements)

References 21 publications

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“…[29] Compound 5, with an amino group at the 5'position, was obtained from thymidine using a reported method. [30] 2',3'-Protected 5'-carboxyadenosine 9 was synthesized from partially protected adenosine 7 (Scheme 3) and the 5'-amino-5'-deoxyadenosine derivative 8 was prepared from adenosine using a literature procedure. [31] The thymidine monomeric units 2 and 3 were coupled separately with 5 through amide bonds to produce modified dinucleosides with nonpolar backbones (Scheme 4) by using a combination of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) as coupling reagent and diisopropylethylamine (DIEA) as the base to obtain fully protected dimers 10 and 12, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…A C H T U N G T R E N N U N G (544AE2) - [38] 5, [30] 6, [28] 7, 8, [31] and 16 [34] and l-Boc-AspA C H T U N G T R E N N U N G (OBzl)OH were prepared following literature procedures. Concentrations of the solutions were determined spectrophotometrically using the following data: for RNase A e 278.5 = 9800 m À1 cm À1 , [39] for 2',3'-cCMP e 268 = 8500 m À1 cm À1 , [40] for angiogenin e 278 = 12 500 m À1 cm À1 , [41] for 6-FAM-dArUdAdA-6-TAMRA e 260 = 102 400 m À1 cm À1 .…”

Section: Resultsmentioning

confidence: 99%

“…5′‐Carboxy thymidine 6 was prepared from partially protected thymidine 4 28 by oxidation of the 5′‐OH group using K 2 S 2 O 8 as the oxidizing agent and RuCl 3 as a catalyst (Scheme ) 29. Compound 5 , with an amino group at the 5′‐position, was obtained from thymidine using a reported method 30. 2′,3′‐Protected 5′‐carboxyadenosine 9 was synthesized from partially protected adenosine 7 (Scheme ) and the 5′‐amino‐5′‐deoxyadenosine derivative 8 was prepared from adenosine using a literature procedure 31…”

Section: Resultsmentioning

confidence: 99%

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Dinucleosides with Non‐Natural Backbones: A New Class of Ribonuclease A and Angiogenin Inhibitors

Debnath¹,

Dasgupta²,

Pathak³

2012

Chemistry A European J

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Ribonuclease A (RNase A) serves as a convenient model enzyme in the identification and development of inhibitors of proteins that are members of the ribonuclease superfamily. This is principally because the biological activity of these proteins, such as angiogenin, is linked to their catalytic ribonucleolytic activity. In an attempt to inhibit the biological activity of angiogenin, which involves new blood vessel formation, we employed different dinucleosides with varied non-natural backbones. These compounds were synthesized by coupling aminonucleosides with dicarboxylic acids and amino- and carboxynucleosides with an amino acid. These molecules show competitive inhibition with inhibition constant (K(i)) values of (59±3) and (155±5) μM for RNase A. The compounds were also found to inhibit angiogenin in a competitive fashion with corresponding K(i) values in the micromolar range. The presence of an additional polar group attached to the backbone of dinucleosides was found to be responsible for the tight binding with both proteins. The specificity of different ribonucleolytic subsites were found to be altered because of the incorporation of a non-natural backbone in between the two nucleosidic moieties. In spite of the replacement of the phosphate group by non-natural linkers, these molecules were found to selectively interact with the ribonucleolytic site residues of angiogenin, whereas the cell binding site and nuclear translocation site residues remain unperturbed. Docked conformations of the synthesized compounds with RNase A and angiogenin suggest a binding preference for the thymine-adenine pair over the thymine-thymine pair.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Dinucleosides with Non‐Natural Backbones: A New Class of Ribonuclease A and Angiogenin Inhibitors

Debnath¹,

Dasgupta²,

Pathak³

2012

Chemistry A European J

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“…Prob lems con nected with for ma tion of H-phosphonamidates from H-phosphonate monoesters and amines 10a-e in the presence of con dens ing agents were cir cum vented by us ing aryl H-phosphonates of type 3. The ease of prep a ra tion, and high sus cep ti bil ity to nucleophilic sub sti tu tion at the phos pho rus cen tre, made aryl H-phosphonates ex cel lent sub strates for syn the sis of nucleoside H-phosphonamidates 12a-e car ry ing pri mary and un hin dered sec ond ary amine moi eties, in cluding dinucleoside H-phosphonamidate 13 [19] (Scheme 5). Due to mild ness of the re ac tion con di tions, the syn thetic pro to col de vel oped can be con sid ered as a gen eral method for the prep a ra tion of nat u ral prod uct an a logues with the P-N bond in a bridg ing po si tion of the phosphoramidate link age.…”

Section: Transesterification Of Aryl Nucleoside H-phosphonates For Mmentioning

confidence: 99%

Nucleoside phosphate analogues of biological interest, and their synthesis via aryl nucleoside H-phosphonates as intermediates.

Cieślak

Sobkowski²,

Jankowska³

et al. 2001

Acta Biochim Pol

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This review presents a brief account of the chemistry and mechanistic aspects of aryl H-phosphonates, and selected applications of this class of compounds as intermediates in the synthesis of a wide range of biologically important analogues of nucleoside phosphates, and oligonucleotides, in which the phosphate moieties are replaced by other structurally related groups. The aryl nucleoside H-phosphonates, compounds of controlled reactivity, have proven to be more versatile and superior to various mixed anhydrides as synthetic intermediates, particularly for preparation of nucleotide analogues bearing P-N or P-S bonds in various configurational arrangements at the phosphate moiety.

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“…In the past two decades, studies on H-phosphonate derivatives have greatly progressed. [16][17][18][19][20][21][22] Advances on the development of a comprehensive H-phosphonate methodology and the underlying chemistry for the preparation of biologically important phosphate esters and their analogues have been discussed by Stawinski and Kraszewski. 20 Stawinski and co-workers have developed H-phosphonate methods to synthesize dideoxynucleotide N3¢→P5¢ phosphoramidates through reaction of nucleoside H-phosphonate monoester with aminonucleoside in the presence of Me 3 SiCl and I 2 21 or exchange of aryl H-phosphonates with aminonucleoside and the following oxidation.…”

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confidence: 99%

Convenient and Efficient Approach to Di- and Trideoxyribonucleotide N3′→P5′ Phosphoramidates

Xu¹,

Huang²,

Fu³

et al. 2005

Synlett

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Arbuzov reaction of phenyl phosphorodichloridite with an equivalent of allyl alcohol and tert-butyl alcohol produced phenyl allyl H-phosphonate and the subsequent ester-exchange with various nucleosides produced nucleoside allyl H-phosphonates. Antherton-Todd reaction of the nucleoside allyl H-phosphonates with 3¢-amino-3¢-deoxythymidine yielded dideoxyribonucleotide N3¢→P5¢ phosphoramidates, and the repetition of this procedure provided trideoxyribonucleotide N3¢→P5¢ phosphoramidates. The method can be used for the synthesis of oligodeoxyribonucleotide N3¢→P5¢ phosphoramidates without any protection for all nucleosides.Oligonucleotide N3¢→P5¢ phosphoramidates have been attracted considerable attention as a class of compounds of potential therapeutic value, 1-6 since these oligonucleotide analogues are resistant towards various nucleases 2,7 and hybridize to complementary DNA or RNA targets with much higher affinity than their natural congeners do. 2 Some synthetic methods of these phosphoramidates have been developed using phosphotriester chemistry, 8 via the Staudinger type of reaction, 9 or by the phosphoramidite method. 4 Gryaznov and co-workers have prepared oligonucleotide N3¢→P5¢ phosphoramidates via oxidative coupling of aminonucleosides with H-phosphonate diesters under Antherton-Todd oxidation conditions. 4,10-13 Stec and co-workers synthesized a kind of compounds by using 2-alkylamino-2-thio-1,3,2-oxathiaphospholanes 14 as the starting material. 15 H-phosphonates are useful intermediates in chemistry, and to find the new synthetic routes to these compounds constitutes a valuable target. In the past two decades, studies on H-phosphonate derivatives have greatly progressed. [16][17][18][19][20][21][22] Advances on the development of a comprehensive H-phosphonate methodology and the underlying chemistry for the preparation of biologically important phosphate esters and their analogues have been discussed by Stawinski and Kraszewski. 20 Stawinski and co-workers have developed H-phosphonate methods to synthesize dideoxynucleotide N3¢→P5¢ phosphoramidates through reaction of nucleoside H-phosphonate monoester with aminonucleoside in the presence of Me 3 SiCl and I 2 21 or exchange of aryl H-phosphonates with aminonucleoside and the following oxidation. 22 However, all these methods required the protection of functional groups in nucleosides. Here we would like to report a convenient and efficient synthesis of dideoxyribonucleotide N3¢→P5¢ phosphoramidates without any protection for nucleosides.Reaction of phenyl phosphorodichloridite (1) with one equivalent of allyl alcohol and one equivalent of tert-butyl alcohol in CH 2 Cl 2 at room temperature under nitrogen atmosphere provided phenyl allyl H-phosphonate diester (2) in 90% yield with minor diallyl H-phosphonate diester appearing (determined by 31 P NMR). The reaction could undergo the formation of the corresponding major tertbutyl phenyl allyl phosphite triester (1¢) and phenyl diallyl phosphate triester (2¢) intermediates, followed by Arbuzov rearrange...

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Aryl H-phosphonates. 10. Synthesis of nucleoside phosphoramidate and nucleoside phosphoramidothioate analogues via H-phosphonamidate intermediates

Cited by 23 publications

References 21 publications

Dinucleosides with Non‐Natural Backbones: A New Class of Ribonuclease A and Angiogenin Inhibitors

Dinucleosides with Non‐Natural Backbones: A New Class of Ribonuclease A and Angiogenin Inhibitors

Nucleoside phosphate analogues of biological interest, and their synthesis via aryl nucleoside H-phosphonates as intermediates.

Convenient and Efficient Approach to Di- and Trideoxyribonucleotide N3′→P5′ Phosphoramidates

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