Novel Acyclic Nucleotides and Nucleoside 5'-Triphosphates Imitating 2',3'-Dideoxy-2',3'-didehydro nucleotides: Synthesis and Biological Properties

Shirokova, Elena A.; Tarussova, N. B.; Shipitsin, Alexander V.; Semizarov, D. G.; Krayevsky, Alexander A.

doi:10.1021/jm00048a010

Cited by 17 publications

(9 citation statements)

References 22 publications

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“…(Z)‐1‐[4‐(phosphonomethoxy)but‐2‐enyl]thymine was synthesized as described in Ref. [3]. Diphosphonic acids were prepared by dissolving the corresponding tetrakis(trimethylsilyl) diphosphonates [5]in aqueous pyridine followed by column chromatography of the obtained emulsion on Dowex 50W4 (H + ) and concentration of the eluted fractions in vacuo.…”

Section: Methodsmentioning

confidence: 99%

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Effect of triphosphate modifications in 2′‐deoxynucleoside 5′‐triphosphates on their specificity towards various DNA polymerases

Martynov¹,

Shirokova²,

Jasko³

et al. 1997

FEBS Letters

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Some natural and glycon-modified dNTPs with P,ypyrophosphate substitution at the triphosphate residue were synthesized and studied to evaluate the effect of these modifications on substrate properties of dNTPs in DNA synthesis catalyzed by human placental DNA polymerases a and P, avian myeloblastosis virus reverse transcriptase, and calf thymus terminal deoxynucleotidyl transferase. Reverse transcriptase proved to be the enzyme least specific to such modifications; the substrate activity of P,y-methylenediphosphonate substituted dTTP and 3'-azido-3'-deoxy-dTTP decreased in the following order: CF 2 = CHF > CBr 2 > CFMe»CH 2 . This order is individual for each DNA polymerase. It is interesting to mention that P,Y-CBr 2 substituted dTTP is neither a substrate nor an inhibitor of DNA polymerase p. This specificity distinguishes DNA polymerase P from other DNA polymerases studied.

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Section: Methodsmentioning

confidence: 99%

“…As a structural basis for III, (Z)‐1‐[4‐(phosphonomethoxy)but‐2‐enyl]thymine was used. Its β,γ‐diphosphate, as well as diphosphates of the corresponding nucleotides with other nucleic bases, selectively terminated DNA synthesis at the catalysis by retroviral reverse transcriptases [3].…”

Section: Introductionmentioning

confidence: 99%

Effect of triphosphate modifications in 2′‐deoxynucleoside 5′‐triphosphates on their specificity towards various DNA polymerases

Martynov¹,

Shirokova²,

Jasko³

et al. 1997

FEBS Letters

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“…The organic phase was washed with H 2 O, dried on anhydrous Na 2 SO 4 , filtered, and evaporated. The residue was purified in an SPE cartridge (silica) eluting with CH 2 Cl 2 /EtOAc to yield 40 mg (53%) of 34 as a white solid: MS (ES, positive mode), m / z 287 (M + 1) + , 309 (M + Na) + ; 1 H NMR was identical to that reported . Anal.…”

Section: Methodsmentioning

confidence: 62%

Acyclic Nucleoside Analogues as Novel Inhibitors of Human Mitochondrial Thymidine Kinase

et al. 2002

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A series of acyclic nucleoside analogues of 5'-O-tritylthymidine have been synthesized and evaluated as potential human mitochondrial thymidine kinase (TK-2) inhibitors. In this series, the sugar moiety of the parent 5'-O-tritylthymidine has been replaced by aliphatic chains including (E)- and (Z)-butenol, butynol, or butanol. Among them the (Z)-butenyl derivative (10) showed an IC(50) against TK-2 of 1.5 microM, being 1 order of magnitude more potent than the parent 5'-O-tritylthymidine. This lead compound has been further modified by replacing the thymine base by other pyrimidine bases such as 5-iodouracil, 5-ethyluracil, 5-methylcytosine, 3-N-methylthymine, or 5,6-dihydrothymine, as well as by the purine base guanine. The trityl group has also been replaced by different aliphatic and aromatic acyl moieties including tert-butylacetyl, hexanoyl, decanoyl, and diphenylacetyl moieties. The evaluation of the compounds against TK-2 and the phylogenetically close HSV-1 TK has shown that the base moiety plays a crucial role in their interaction against these pyrimidine nucleoside kinases. Also, the presence of a lipophilic substituent, preferentially an aromatic moiety such as diphenylmethyl or triphenylmethyl, is required for efficient TK-2 inhibition. Whereas some compounds showed marked specificity for either TK-2 (i.e, the 5,6-dihydrothymine derivative, 26) or HSV-1 TK (i.e., the butynyl derivative, 11), some others, including the (Z)-and (E)-butenyl derivatives 10 and 12, showed significant inhibition against both enzymes. They also proved to be inhibitory against HSV-1 TK in intact human osteosarcoma cells that were transduced with the HSV-1 TK gene.

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“…An alternative synthesis of structures 26 involved the coupling of 1,4-dichloroalkene with a nucleic base followed by the reaction with an appropriate phosphonate component and deprotection [34].…”

Section: Analogues With Limited Flexibility Of the Side Chainmentioning

confidence: 99%

The Synthesis and Antiviral Properties of Acyclic Nucleoside Analogues with a Phosphonomethoxy Fragment in the Side Chain

Khandazhinskaya

Yas'ko²,

Shirokova³

2006

CMC

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Acyclic nucleoside analogues bearing phosphonomethoxy residues in the side chain (ANP) attract much attention due to a very beneficial combination of biological properties. Intensive work of organic chemists during the last two decades resulted in a large panel of new compounds that were evaluated as potential antiviral drugs. Herein, we present an overview of major chemical structures within the group of acyclic nucleoside analogues containing phosphonomethoxy side fragments and describe main aspects of their synthesis and antiviral potential. We also describe progress in "prodrug" approaches applied to this chemical group to improve pharmacokinetic profiles of the potential candidates. Chemical modifications in the molecule of parental ANP aimed at blocking of phosphonate charges resulted in a set of promising derivatives, two of which have been recently approved for treatment of hepatits B (Hepsera) and HIV (Viread). The preparation, antiviral properties and some aspects of metabolic transformations and pharmacokinetics of ANP prodrugs are discussed.

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Novel Acyclic Nucleotides and Nucleoside 5'-Triphosphates Imitating 2',3'-Dideoxy-2',3'-didehydro nucleotides: Synthesis and Biological Properties

Cited by 17 publications

References 22 publications

Effect of triphosphate modifications in 2′‐deoxynucleoside 5′‐triphosphates on their specificity towards various DNA polymerases

Effect of triphosphate modifications in 2′‐deoxynucleoside 5′‐triphosphates on their specificity towards various DNA polymerases

Acyclic Nucleoside Analogues as Novel Inhibitors of Human Mitochondrial Thymidine Kinase

The Synthesis and Antiviral Properties of Acyclic Nucleoside Analogues with a Phosphonomethoxy Fragment in the Side Chain

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