Determination of formation constants of calcium complexes of difluoromethylenediphosphonic acid and related diphosphonates

Fonong, Tekum; Burton, Donald J.; Pietrzyk, Donald J.

doi:10.1021/ac00258a025

Cited by 43 publications

(24 citation statements)

References 41 publications

(38 reference statements)

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“…16,17 Fosfomycin, a phosphonate containing natural product isolated from soil bacteria in 1969, has broad spectrum antibacterial activity. 18 Dichloromethylene diphosphonic acid (chlodronic acid) has been shown to inhibit RNA polymerase activity in influenza, 19 and both the related mono-and difluoromethylene diphosphonates have shown activity as bone lysis inhibitors 20 and antiviral agents. 21,22 Methylene phosphonates have been devised as nonhydrolyzable mimics of phosphates to probe a variety of biological systems.…”

Section: ■ Introductionmentioning

confidence: 99%

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: 99%

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

et al. 2013

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“…A correlation between increasing acidity and antiresorptive activity of BPs has been reported [30]. Yet a strongly acidic BP such as 1,1,2,2-tetrafluoroethane-1,2-bisphosphonate (pKa 1 ‫ס‬ 1.07; pKa 2 ‫ס‬ 1.97, pKa 3 ‫ס‬ 4.49, pKa 4 ‫ס‬ 6.30) [31], was not found active as an inhibitor of bone resorption [32]. We synthesized bisphosphonate 6, with a chain length similar to that of AdBP, with difluoro groups replacing the keto groups in positions next to the phos-phonic groups.…”

Section: Figurementioning

confidence: 98%

“…The disodium salt was filtered off, washed, and dried to give a yield of 0.35 g, 71%. NMR (D 2 O) 1 H: d ‫ס‬ 2.66 (t, 4H, J ‫ס‬ 6.9 Hz), 3.02 (t, 4H, J ‫ס‬ 6.9 Hz) 31. P: d ‫ס‬ ‫71.2מ‬ (s).…”

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Long-chain functional bisphosphonates: synthesis, anticalcification, and antiresorption activity

Chen¹,

Schlossman²,

Breuer³

et al. 2000

Heteroatom Chem.

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Bisacylphosphonates have previously been shown to possess in vitro activity with regard to hydroxyapatite (HAP) formation and dissolution, and in vivo on tissue calcification and bone resorption. This work was aimed at elucidating the role of the keto groups in the biological activity of these compounds. For this purpose, we have synthesized a series of long‐chain bisphosphonates possessing different functional groups adjacent to the phosphonic functions and examined them in some in vitro and in vivo models. The functional groups introduced into the newly synthesized bisphosphonates (hydroxyl, amide, and difluoromethylene) were chosen as to represent certain isolated aspects of the keto groups in the original compounds. None of the functional groups introduced into the long chain bisphosphonates bestowed higher activity on the molecules than the carbonyl groups. The unique effect of the α‐keto groups in rendering long‐chain bisphosphonates active is presumably attained through a combination of chelating ability with sufficiently low pKa values to enable the bisacylphosphonate molecules to be fully ionized at physiological pH. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:470–479, 2000

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“…The stability constants derived from potentiometric titrations of Ca 2+ complexes (given as log β of complexes created in solution) are often studied with respect to other biologically relevant metal ions; transition and alkaline earth metal ions giving a general sequence of stability, which identifies Ca 2+ as one of the weakest: transition metal ions≫Mg 2+ >Ca 2+ >Li + ∼Na + ∼K + …”

Section: Introductionmentioning

confidence: 99%

“…It was proven via potentiometry that clodronate (NN‐BP; Figure ) forms equimolar complexes as well as dimeric species Ca 2 L. This was studied in a broad pH range (2–11) in aqueous solution (values of log β listed in Table S1) . In solid state, four examples—one monomeric and three polymeric structures—of clodronate complexes with Ca 2+ ions were characterized by single‐crystal X‐ray diffraction.…”

Section: Introductionmentioning

confidence: 99%

Interactions between Clinically Used Bisphosphonates and Bone Mineral: from Coordination Chemistry to Biomedical Applications and Beyond

Gałęzowska

2018

ChemMedChem

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Bisphosphonates (BPs) are well-established, widely used first-choice drugs for bone-related diseases and are one of the few classes of molecules for selective bone targeting. Their binding to calcium cations within hydroxyapatite (HA) is a key physicochemical event that takes place on the bone surface. It is the starting point for a cascade of biochemical reactions and cellular effects that lead to the pharmacological activity of BPs. The phenomenon has been known for years, yet its physicochemical nature is still not fully understood. In particular, the adsorption/release processes and structure-function relationships of BPs remain to be clarified. These are elementary, yet crucial factors, which should influence the design and development of new delivery tools or drugs with improved characteristics. This review summarizes the current understanding of the chemical interactions between clinically used BPs and bone mineral, starting from basic Ca coordination chemistry through to interactions with hydroxyapatite, nanocrystalline apatites, and natural bone mineral.

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Determination of formation constants of calcium complexes of difluoromethylenediphosphonic acid and related diphosphonates

Cited by 43 publications

References 41 publications

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

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

Long-chain functional bisphosphonates: synthesis, anticalcification, and antiresorption activity

Interactions between Clinically Used Bisphosphonates and Bone Mineral: from Coordination Chemistry to Biomedical Applications and Beyond

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