Synthesis and characterization of a new fluorine-substituted nonionic dinucleoside phosphonate analog. P-Deoxy-P-(difluoromethyl)thymidylyl(3' .fwdarw. 5')thymidine

Bergstrom, D. E.; Shum, Patrick

doi:10.1021/jo00252a014

Cited by 47 publications

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“…Unless otherwise mentioned, all reagents were purchased from commercial sources. Diethyl (difluoromethyl) phosphonate was prepared from chlorodifluoromethane and triethylphsophite according to a known procedure (42). Absolute THF was obtained by distillation from sodium.…”

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confidence: 99%

Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid

Prakash

Zibinsky

Upton

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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It is difficult to overestimate the importance of nucleoside triphosphates in cellular chemistry: They are the building blocks for DNA and RNA and important sources of energy. Modifications of biologically important organic molecules with fluorine are of great interest to chemists and biologists because the size and electronegativity of the fluorine atom can be used to make defined structural alterations to biologically important molecules. Although the concept of nonhydrolyzable nucleotides has been around for some time, the progress in the area of modified triphosphates was limited by the lack of synthetic methods allowing to access bisCF 2 -substituted nucleotide analogs-one of the most interesting classes of nonhydrolyzable nucleotides. These compounds have "correct" polarity and the smallest possible steric perturbation compared to natural nucleotides. No other known nucleotides have these advantages, making bisCF 2 -substituted analogs unique. Herein, we report a concise route for the preparation of hitherto unknown highly acidic and polybasic bis(difluoromethylene)triphosphoric acid 1 using a phosphorous(III)/phosphorous(V) interconversion approach. The analog 1 compared to triphosphoric acid is enzymatically nonhydrolyzable due to substitution of two bridging oxygen atoms with CF 2 groups, maintaining minimal perturbations in steric bulkiness and overall polarity of the triphosphate polyanion. The fluorinated triphosphoric acid 1 was used for the preparation of the corresponding fluorinated deoxynucleotides (dNTPs). One of these dNTP analogs (dT) was demonstrated to fit into DNA polymerase beta (DNA pol β) binding pocket by obtaining a 2.5 Å resolution crystal structure of a ternary complex with the enzyme. Unexpected dominating effect of triphosphate∕Mg 2þ interaction over Watson-Crick hydrogen bonding was found and discussed.DNA polymerase beta | nonhydrolyzable nucleotides | fluorinated triphosphate | pentabasic acid | isopolarity and bioisotericity

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confidence: 99%

Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid

Prakash

Zibinsky

Upton

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…112 Blackburn and colleagues 113 improved the synthesis of such compounds and their methodology was later used in the construction of analogously modified dinucleotides. 114…”

Section: Cnps With Fluorine Atom(s) At Phosphonate α-Carbonmentioning

confidence: 99%

Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

Baszczyňski

Janeba

2013

Medicinal Research Reviews

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The fluorine atom plays an important role in medicinal chemistry because fluorine substitution has a strong impact on the physical, chemical, and biological properties of bioactive compounds. Such fluorine modifications have also been extensively studied among the pharmaceutically important class of nucleoside phosphonates, nucleotide analogues in which the phosphate group is replaced by the enzymatically and chemically stable phosphonate moiety. The fluorinated nucleoside phosphonates abound with antiviral, antiparasitic, and anticancer properties because they are able to act as inhibitors of important enzymes of nucleoside/nucleotide metabolism. In this paper, we review the biological properties of cyclic and acyclic nucleoside phosphonates modified by the attachment of one or more fluorine atoms to various parts of the molecule, namely to nucleobases, alkylphosphonate groups, cyclic or acyclic linkers, or to prodrug moieties.

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“…In our case, none of the previously reported methods [PCl 3 , AlCl 3 , CFBr 3 , H 2 O); 12 (iPrO) 2 P(O)CFBr 2 , PCl 5 , P(O)Cl 3 ); 13 (iPrO) 2 P(O)CFBr 2 , SOCl 2 , DMF 14 ] allowed the preparation of the expected compound. Finally we successfully applied the methodology developed by Bergstrom 15 based on the reaction between diisopropyl dibromofluoromethylphosphonate 1, thionyl chloride (10.3 eq.) and pyridine (0.15 eq.).…”

Section: Synthesis Of Dibromofluoromethylphosphonamides 3 Derived Fro...mentioning

confidence: 99%

Attempts at asymmetric electrosynthesis of α-fluorinated cyclopropylphosphonamides

Goumain

Oulyadi

Jubault

et al. 2001

J. Chem. Soc., Perkin Trans. 1

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published as an Advance Article on the web 14th March 2001Variously N,N-disubstituted chiral dibromofluoromethylphosphonamides 3 were easily prepared and used for the asymmetric electrosynthesis, in the presence of tert-butyl acrylate, of α-fluorinated cyclopropylphosphonamides 7. The diastereoisomeric excesses are moderate (up to 40%). Moreover, the identification of the trans and cis stereoisomers has been deduced from analysis of 2D 1 H-19 F HOESY spectra.

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Synthesis and characterization of a new fluorine-substituted nonionic dinucleoside phosphonate analog. P-Deoxy-P-(difluoromethyl)thymidylyl(3' .fwdarw. 5')thymidine

Cited by 47 publications

References 0 publications

Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid

Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid

Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

Attempts at asymmetric electrosynthesis of α-fluorinated cyclopropylphosphonamides

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