Fluorinated Phosphonates:  Synthesis and Biomedical Application

Romanenko, V. D.; Kukhar, V. P.

doi:10.1021/cr051000q

Cited by 343 publications

(191 citation statements)

References 427 publications

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“…23 Difluoromethylene phosphonates are often prepared as phosphate mimics due to the variety of applicable synthetic methods. 17 The inductive effects of two fluorine atoms results in pK a 2v a l u e s between 5.0 and 6.0, which are much lower than the pK a 2v a l u e s of physiological phosphates. The preparation of monofluoromethylene phosphonates is much less widespread, in part due to synthetic complexity.…”

Section: ■ Introductionmentioning

confidence: 98%

“…21,22 Methylene phosphonates have been devised as nonhydrolyzable mimics of phosphates to probe a variety of biological systems. 16, 17 Blackburn first proposed halogenation of the methylene phosphonate functionality in an effort to better mimic the properties of the natural phosphate. 23 Difluoromethylene phosphonates are often prepared as phosphate mimics due to the variety of applicable synthetic methods.…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis and Evaluation of l-Rhamnose 1C-Phosphonates as Nucleotidylyltransferase Inhibitors

et al. 2013

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/npsi/ctrl?lang=en http://nparc.cisti-icist.nrc-cnrc.gc.ca/npsi/ctrl?lang=fr Access and use of this website and the material on it are subject to the Terms and Conditions set forth at http://nparc.cisti-icist.nrc-cnrc.gc.ca/npsi/jsp/nparc_cp.jsp?lang=en NRC Publications Archive Archives des publications du CNRCThis publication could be one of several versions: author's original, accepted manuscript or the publisher's version. / La version de cette publication peut être l'une des suivantes : la version prépublication de l'auteur, la version acceptée du manuscrit ou la version de l'éditeur. For the publisher's version, please access the DOI link below./ Pour consulter la version de l'éditeur, utilisez le lien DOI ci-dessous.http://dx.doi.org/10.1021/jo401542sThe Journal of Organic Chemistry, 78, 19, pp. 9822-9833, 2013-09-10 ABSTRACT: We report the synthesis of a series of phosphonates and ketosephosphonates possessing an L-rhamnose scaffold with varying degrees of fluorination. These compounds were evaluated as potential inhibitors of α-D-glucose 1-phosphate thymidylyltransferase (Cps2L), the first enzyme in Streptococcus pneumoniae L-rhamnose biosynthesis, and a novel antibiotic target. Enzyme−substrate and enzyme−inhibitor binding experiments were performed using water-ligand observed binding via gradient spectroscopy (WaterLOGSY) NMR for known sugar nucleotide substrates and selected phosphonate analogues. IC 50 values were measured and K i values were calculated for inhibitors. New insights were gained into the binding promiscuity of enzymes within the prokaryotic L-rhamnose biosynthetic pathway (Cps2L, RmlB−D) and into the mechanism of inhibition for the most potent inhibitor in the series, L-rhamnose 1C-phosphonate. ■ INTRODUCTIONStreptococcus pneumoniae is a prevalent, highly infectious, Gram-positive pathogen that has shown high clinical resistance to penicillin and chloramphenicol. 1 The mechanisms of resistance for S. pneumoniae and other more invasive pathogens, including Mycobacterium tuberculosis, usually entail alterations to drug target proteins involved in cell wall synthesis. 2−5 Bacterial chemo-resistance, including resistance to synergistic treatments using β-lactams and aminoglycosides, is a growing barrier to the treatment of invasive pathogens (i.e., S. pneumoniae and M. tuberculosis). 6 Cell wall biosynthesis is a commonly pursued target for a variety of bacterial enzyme inhibitors as cell wall assembly is essential for bacterial survival and virulence. L-Rhamnose (6-deoxy-L-mannose) serves as the linking unit between arabinogalactan and peptidoglycan 7,8 and is a necessary constituent of the bacterial cell wall in many bacterial species. 9 The biosynthesis of L-rhamnose begins with nucleotidylyltransferase enzymes (Cps2L/RmlA) responsible for generating activated sugars in the form of glycosylated nucleoside diphosphates (NDPs). These NDPs are generated from the enzymatic coupling of sugar 1-phosphates with nucleoside triphosphates (NTPs). Once formed, the NDPs may be further modified ...

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Section: ■ Introductionmentioning

confidence: 98%

Section: ■ Introductionmentioning

confidence: 99%

Synthesis and Evaluation of l-Rhamnose 1C-Phosphonates as Nucleotidylyltransferase Inhibitors

et al. 2013

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“…5 To address these issues, the difluoromethylphosphonate (or difluorophosphonate, pCF 2 ) derivatives and difluorophosphonic acid have been considered as interesting candidates for pharmaceutical and biomaterials applications [5][6][7][8][9] due to their resistance toward enzyme degradation and water hydrolysis. 6,[10][11][12] Additionally, difluorophosphonic acid is a stronger acid than phosphonic or phosphoric acids. 10 As long-standing interest in our laboratory, we were pioneers in the development of pCF 2 -functionalized monomers and polymers as potent self etching primers for dental applications.…”

Section: Introductionmentioning

confidence: 99%

“…6,[10][11][12] Additionally, difluorophosphonic acid is a stronger acid than phosphonic or phosphoric acids. 10 As long-standing interest in our laboratory, we were pioneers in the development of pCF 2 -functionalized monomers and polymers as potent self etching primers for dental applications. 5,9 Recently, we reported well-defined pCF 2 -functionalized polymers synthesized by reversible additionfragmentation chain transfer polymerization, in which the pCF 2 group was not only introduced into the polymer backbone but also at the macromolecular chain-ends.…”

Section: Introductionmentioning

confidence: 99%

A straightforward synthesis of well‐defined difluorophosphonylated terminated poly(ε‐caprolactone) for grafting onto iron oxide magnetic nanoparticles

Pascual

Livi

et al. 2016

J. Polym. Sci. Part A: Polym. Chem.

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“…[26][27][28][29] Moreover, -aminophosphonates have broad applications due to their biological activity [29][30][31][32][33] such as antibacterial, 34,35 anti-cancer, 36 antiviral, and as enzyme inhibitors. 37,38 We have successful used our strategy for tandem amination/alkynylation, amination/cyanation, and amination/trifluoromethylation.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N-heterocycles through cyclization-triggered tandem additions to alkynes and the study of promoters in ionic reactions.

Han¹

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Fluorinated Phosphonates: Synthesis and Biomedical Application

Cited by 343 publications

References 427 publications

Synthesis and Evaluation of l-Rhamnose 1C-Phosphonates as Nucleotidylyltransferase Inhibitors

Synthesis and Evaluation of l-Rhamnose 1C-Phosphonates as Nucleotidylyltransferase Inhibitors

A straightforward synthesis of well‐defined difluorophosphonylated terminated poly(ε‐caprolactone) for grafting onto iron oxide magnetic nanoparticles

Synthesis of N-heterocycles through cyclization-triggered tandem additions to alkynes and the study of promoters in ionic reactions.

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