Synthesis of a potent inhibitor of HIV reverse transcriptase

Hamilton, Chris J.; Roberts, Stanley M.; Shipitsin, Alexander V.

doi:10.1039/a801127c

Cited by 32 publications

(26 citation statements)

References 6 publications

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“…Unlike α, β–CXY dNTP analogues,18 these compounds are substrates of the polymerase, but release a substituted bisphosphonate in place of the natural pyrophosphate leaving group. Several β,γ -CXY nucleotide analogues were previously investigated in studies of DNA, viral RNA or RNA-directed DNA polymerases,4,5,7,10–13,19 but the structures of the putative complexes formed were not determined. The obtention of diastereomeric mixtures owing to the generation of a new chiral center when X ≠ Y in such analogues, and the resulting potential for a stereospecific interaction with the enzyme active site, was not addressed in these studies 10,11,13.…”

Section: Introductionmentioning

confidence: 99%

Halogenated β,γ-Methylene- and Ethylidene-dGTP-DNA Ternary Complexes with DNA Polymerase β: Structural Evidence for Stereospecific Binding of the Fluoromethylene Analogues

et al. 2010

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Abstractβ,γ-Fluoromethylene analogues of nucleotides are considered to be useful mimics of the natural substrates, but direct structural evidence defining their active site interactions has not been available, including the influence of the new chiral center introduced at the CHF carbon, as in β,γ-fluoromethylene-dGTP, which forms a active site complex with DNA polymerase β, a repair enzyme that plays an important role in base excision repair (BER) and oncogenesis. We report X-ray crystallographic results for a series of β,γ-CXY dGTP analogues, where X,Y = H, F, Cl, Br, and/or CH 3 . For all three monofluorinated analogues examined (CHF, 3/4; CCH 3 F , 13/14; CClF 15/16), a single CXF-diastereomer (3, 13, 15) is observed in the active site complex, with the CXF fluorine atom at a ~3 Å (bonding) distance to a guanidinium N of Arg183. In contrast, for the CHCl, CHBr and CHCH 3 analogues, both diasteromers (6/7, 8/9, 10/11) populate the dGTP site in the enzyme complex about equally. The structures of the bound dichloro (5) and dimethyl (12) analogue complexes indicate little to no steric effect on the placement of the bound nucleotide backbone. The results suggest that introduction of a single fluorine atom at the β,γ-bridging carbon atom of these dNTP analogues enables a new, stereospecific interaction within the pre-organized active site complex that is unique to fluorine. The results also provide the first diverse structural dataset permitting an assessment of how closely this class of dNTP analogues mimics the conformation of the parent nucleotide within the active site complex.

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Section: Introductionmentioning

confidence: 99%

Halogenated β,γ-Methylene- and Ethylidene-dGTP-DNA Ternary Complexes with DNA Polymerase β: Structural Evidence for Stereospecific Binding of the Fluoromethylene Analogues

et al. 2010

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“…Only a few methods for attaching low nucleophilicity phosphates to the 5′-carbon of a nucleoside are known (14,15). These methods include the Mitsunobu reaction (8,(16)(17)(18), couplings promoted by DCC and other dehydrating agents (19,20), electrophilic phosphorylation developed by Yoshikawa, Ludwig, and Eckstein employing 2-chloro-4H-1,3, 2-benzodioxaphosphorin-4-one (21)(22)(23)(24), nucleophilic cleavage of phosphoryl anhydride (25), reactions involving phosphoramidates (19,(26)(27)(28)(29)(30)), Blackburn's method employing nucleophilic substitution at 5′ position (31)(32)(33), and enzymatic phosphorylation (20,34,35). All of these methods lack versatility and their success depends on many factors, such as nucleophilicity/electrophilicity of the phosphate source, steric bulkiness, stability of the product under acidic or basic conditions, etc.…”

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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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“…5 Additionally, α-halogenated alkylidenediphosphonates result in more active compounds than the parent structure in organic synthesis 1,6-11 and particular biological systems. [12][13] Common methods for the preparation of α-monohalogenated methylenediphosphonates include the partial reduction of dihalogenated methylenediphosphonates, 14 [23][24][25][26] Developing general methods for the preparation of elaborated methylenediphosphonates, especially those tolerating substituents such as alkyl group or halogen atom on the α-carbon position is of great interest. The successful application of LDA process for the synthesis of α-lithiated alkylidenediphosphonates has confirmed its efficiency in the synthesis of alkylidenediphosphonates and (E)-vinylphosphonates with a considerable degree of stereoselectivity.…”

Section: A Facile Approach For the Synthesis Of α -Halogenated Alkylimentioning

confidence: 99%

A Facile Approach for the Synthesis of Α -Halogenated Alkylidenediphosphonates by Reaction of Alkyllithium With Chlorophosphate and Halogen Reagent

Lai

2004

Phosphorus, Sulfur, and Silicon and the Related Elements

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Synthesis of a potent inhibitor of HIV reverse transcriptase

Cited by 32 publications

References 6 publications

Halogenated β,γ-Methylene- and Ethylidene-dGTP-DNA Ternary Complexes with DNA Polymerase β: Structural Evidence for Stereospecific Binding of the Fluoromethylene Analogues

Halogenated β,γ-Methylene- and Ethylidene-dGTP-DNA Ternary Complexes with DNA Polymerase β: Structural Evidence for Stereospecific Binding of the Fluoromethylene Analogues

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

A Facile Approach for the Synthesis of Α -Halogenated Alkylidenediphosphonates by Reaction of Alkyllithium With Chlorophosphate and Halogen Reagent

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