- Ratiometric pH Imaging with a CoII2 MRI Probe via CEST Effects of Opposing pH Dependences
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We report a Co2-based magnetic resonance (MR) probe that enables the ratiometric quantitation and imaging of pH through chemical exchange saturation transfer (CEST). This approach is illustrated in a series of air- and water-stable CoII2 complexes featuring CEST-active tetra(carboxamide) and/or hydroxyl-substituted bisphosphonate ligands. For the complex bearing both ligands, variable-pH CEST and NMR analyses reveal highly shifted carboxamide and hydroxyl peaks with intensities that increase and decrease with increasing pH, respectively. The ratios of CEST peak intensities at 104 and 64 ppm are correlated with solution pH in the physiological range 6.5-7.6 to construct a linear calibration curve of log(CEST104 ppm/CEST64 ppm) versus pH, which exhibits a remarkably high pH sensitivity of 0.99(7) pH unit-1 at 37 °C. In contrast, the analogous CoII2 complex with a CEST-inactive bisphosphonate ligand exhibits no such pH response, confirming that the pH sensitivity stems from the integration of amide and hydroxyl CEST effects that show base- and acid-catalyzed proton exchange, respectively. Importantly, the pH calibration curve is independent of the probe concentration and is identical in aqueous buffer and fetal bovine serum. Furthermore, phantom images reveal analogous linear pH behavior. The CoII2 probe is stable toward millimolar concentrations of H2PO4-/HPO42-, CO32-, SO42-, CH3COO-, and Ca2+ ions, and more than 50% of melanoma cells remain viable in the presence of millimolar concentrations of the complex. The stability of the probe in physiological environments suggests that it may be suitable for in vivo studies. Together, these results highlight the ability of dinuclear transition metal PARACEST probes to provide a concentration-independent measure of pH, and they provide a potential design strategy toward the development of MR probes for ratiometric pH imaging.
- Thorarinsdottir, Agnes E.,Du, Kang,Collins, James H. P.,Harris, T. David
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- New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors
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Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P1,P4-di(adenosine-5′) tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents.
- Yanachkov, Ivan B.,Chang, Hung,Yanachkova, Milka I.,Dix, Edward J.,Berny-Lang, Michelle A.,Gremmel, Thomas,Michelson, Alan D.,Wright, George E.,Frelinger, Andrew L.
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- Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways
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Bisphosphonates are a major class of drugs used to treat osteoporosis, Paget's disease, and cancer. They have been proposed to act by inhibiting one or more targets including protein prenylation, the epidermal growth factor receptor, or the adenine nucleotide translocase. Inhibition of the latter is due to formation in cells of analogs of ATP: the isopentenyl ester of ATP (ApppI) or an AppXp-type analog of ATP, such as AMP-clodronate (AppCCl2p). We screened both ApppI as well as AppCCl2p against a panel of 369 kinases finding potent inhibition of some tyrosine kinases by AppCCl2p, attributable to formation of a strong hydrogen bond between tyrosine and the terminal phosphonate. We then synthesized bisphosphonate preprodrugs that are converted in cells to other ATP-analogs, finding low nM kinase inhibitors that inhibited cell signaling pathways. These results help clarify our understanding of the mechanisms of action of bisphosphonates, potentially opening up new routes to the development of bone resorption, anticancer, and anti-inflammatory drug leads.
- Malwal, Satish R.,O'Dowd, Bing,Feng, Xinxin,Turhanen, Petri,Shin, Christopher,Yao, Jiaqi,Kim, Boo Kyung,Baig, Noman,Zhou, Tianhui,Bansal, Sandhya,Khade, Rahul L.,Zhang, Yong,Oldfield, Eric
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supporting information
p. 7568 - 7578
(2018/05/31)
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- Transition state in DNA polymerase β Catalysis: Rate-Limiting chemistry altered by base-pair configuration
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Kinetics studies of dNTP analogues having pyrophosphate-mimicking β,β-pCXYp leaving groups with variable X and Y substitution reveal striking differences in the chemical transition-state energy for DNA polymerase β that depend on all aspects of base-pairing configurations, including whether the incoming dNTP is a purine or pyrimidine and if base-pairings are right (T*A and G*C) or wrong (T*G and G*T). Br?nsted plots of the catalytic rate constant (log(kpol)) versus pKa4 for the leaving group exhibit linear free energy relationships (LFERs) with negative slopes ranging from -0.6 to -2.0, consistent with chemical rate-determining transition-states in which the active-site adjusts to charge-stabilization demand during chemistry depending on base-pair configuration. The Br?nsted slopes as well as the intercepts differ dramatically and provide the first direct evidence that dNTP base recognition by the enzyme-primer-template complex triggers a conformational change in the catalytic region of the active-site that significantly modifies the rate-determining chemical step.
- Oertell, Keriann,Chamberlain, Brian T.,Wu, Yue,Ferri, Elena,Kashemirov, Boris A.,Beard, William A.,Wilson, Samuel H.,McKenna, Charles E.,Goodman, Myron F.
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p. 1842 - 1848
(2014/04/17)
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- SYNTHESIS AND HIV-1 REVERSE TRANSCRIPTASE INHIBITION ACTIVITY OF FUNCTIONALIZED PYROPHOSPHATE ANALOGUES
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A new approach, ketone derivatization, for introducing desired functionality into the α-keto pyrophosphate analogues oxophosphonoacetic acid (COPAA) and oxomethanediphosphonic acid (COMDP) is exemplified in the synthesis of several COPAA and COMDP hydrazones with specific functional groups.The preparation of tetraalkyl COMDP esters is also described.Inhibition of HIV-1 reverse transcriptase (isolated enzyme) and of p24 production by HIV-1 (virus-infected H9 cells) by hydrazone derivatives of COPAA and COMDP is briefly discussed.
- McKenna, Charles E.,Khare, Anil,Ju, Jing-Yue,Li, Zeng-Min,Duncan, Greg,et al.
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p. 139 - 142
(2007/10/02)
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- SYNTHESIS OF α-HALOGENATED METHANEDIPHOSPHONATES
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Methanediphosphonate (MDP) anions can exhibit anti-viral activity, inhibit bone resorption, and act as ligands in radiopharmaceuticals. α-Halo-substitution provides MDP derivatives (XYMPD, where X = H, F, Cl or Br; Y = F, Cl or Br) with modified acid-base, steric and other properties.These compounds are conveniently made from the corresponding α-halogenated XYMDP esters (RO)2P(O)CXYP(O)(OR)2.Detailed procedures are given for synthesis of R4XYMDP for R = Pri and X, Y = H, Cl; Cl, Cl; H, Br; Br, Br; F, Cl; F, Br and Cl, Br in 88-96percent yield; for R = Et and X, Y = H, Cl; Cl, Cl; H, Br; Br, Br and Cl, F in 81-94percent yield; and for R = Me and X, Y = Cl, Cl and Br, Br in 72-80percent yield.NMR data (1H, 31P,13C, (19F)) are presented for the products obtained.The XYMDP acids (X, Y = H, Cl; Cl, Cl; H, Br; Br, Br; F, Cl; F, Br and Cl, Br) were prepared by HCl hydrolysis of a corresponding ester and characterized as tris(dicyclohexylammonium) salts by elemental analyses and 31P NMR.
- McKenna, Charles E.,Khawli, Leslie A.,Ahmad, Wan-Yaacob,Pham, Phuong,Bongartz, Jean-Pierre
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- Ttrihalogenomethylsulphenylation of Tetraisopropyl Methylenebisphosphonates
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Trihalogenomethylthiomethylenebisphosphonates, 2CRSCClnF(3-n) (n = 0-2; R = H, Me), are formed by reaction of salts of tetraisopropyl methylenebisphosphonates, 2CRM (M = Li, Na; R = H, Me), with trihalogenomethanesulphenyl chlorides, CClnF(3-n)SCl (n = 0-2).The ester products are transesterified with bromotrimethylsilane and hydrolysed with aqueous methanolic sodium hydroxide to give the corresponding tetrasodium salts of the bisphosphonic acids.The sulphenylation reactions are complex and are facilitated by the use of Lewis acids.Sulphenylations using chlorodifluoro- and dichloro-methanesulphenyl chlorides afford unexpected additional produts arising from chlorine replacement by fluorine.
- Blackburn, G. Michael,Maciej, Thomas W.
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p. 1935 - 1940
(2007/10/02)
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- SYNTHESIS OF ALKYLATED METHYLENE BISPHOSPHONATES VIA ORGANOTHALLIUM INTERMEDIATES
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Thallium(I) derivatives of esterified methylene bisphosphonates can be readily obtained by treating the latter with thallium(I) ethoxide under anhydrous conditions.Alkylation of the thallium(I) derivatives by a range of primary alkyl iodides takes place smoothly, and significantly higher yields are obtained than for the corresponding reactions with lithio or sodio derivatives.
- Hutchinson, David W.,Semple, Graeme
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p. 145 - 152
(2007/10/02)
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