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Vincent Massey - One of the best experts on this subject based on the ideXlab platform.
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use of 8 substituted fad analogues to investigate the hydroxylation mechanism of the flavoprotein 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Biochemistry, 2004Co-Authors: Pimchai Chaiyen, Vincent Massey, Jeerus Sucharitakul, Jisnuson Svasti, Barrie Entsch, David P BallouAbstract:2-Methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (MHPCO) is a flavoprotein that catalyzes the oxygenation of MHPC to form α-(N-acetylaminomethylene)-succinic acid. Although formally similar to the oxygenation reactions catalyzed by phenol hydroxylases, MHPCO catalyzes the oxygenation of a pyridyl derivative rather than a simple phenol. Therefore, in this study, the mechanism of the reaction was investigated by replacing the natural cofactor FAD with FAD analogues having various substituents (−Cl, −CN, −NH2, −OCH3) at the C8-position of the isoalloxazine. Thermodynamic and catalytic properties of the reconstituted enzyme were investigated and found to be similar to those of the native enzyme, validating that these FAD analogues are reasonable to be used as mechanistic probes. Dissociation constants for the binding of MHPC or the substrate analogue 5-hydroxynicotinate (5HN) to the reconstituted enzymes indicate that the reconstituted enzymes bind well with ligands. Redox potential values of the...
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reaction of 2 methyl 3 Hydroxypyridine 5 carboxylic acid mhpc oxygenase with n methyl 5 hydroxynicotinic acid studies on the mode of binding and protonation status of the substrate
Biochemistry, 1997Co-Authors: Pimchai Chaiyen, Pierre Brissette, David P Ballou, Vincent MasseyAbstract:Titrations of 2-methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase with the substrate MHPC identified the MHPC species bound to the enzyme as the tripolar ionic species. This result was supported by studies of the binding to the enzyme of N-methyl-5-hydroxynicotinic acid (NMHN), an MHPC analog existing only in the tripolar ionic form. The Kd is 55 μM compared to a Kd of 9.2 μM for MHPC and 5.2 μM for 5-hydroxynicotinic acid. Kinetics studies of the binding of NMHN to MHPC oxygenase show that its binding, like that for MHPC and for 5HN, is also a two-step process. Since NMHN never exists as an anionic form, neither of the observed steps is due to the binding of an anionic species as an intermediate step. Investigations of the reduction and oxygenation half reactions demonstrate that the mechanism of catalysis with NMHN is basically the same as with MHPC or with 5-hydroxynicotinic acid. Product analysis from reactions using NMHN, a compound that possesses positive charge on the nitrogen atom, indic...
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gene cloning sequence analysis and expression of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Pimchai Chaiyen, David P Ballou, Vincent MasseyAbstract:The gene encoding 2-methyl-3-Hydroxypyridine-5-carboxylic acid oxygenase (MHPCO; EC 1.14.12.4) was cloned by using an oligonucleotide probe corresponding to the N terminus of the enzyme to screen a DNA library of Pseudomonas sp. MA-1. The gene encodes for a protein of 379 amino acid residues corresponding to a molecular mass of 41.7 kDa, the same as that previously estimated for MHPCO. MHPCO was expressed in Escherichia coli and found to have the same properties as the native enzyme from Pseudomonas sp. MA-1. This study shows that MHPCO is a homotetrameric protein with one flavin adenine dinucleotide bound per subunit. Sequence comparison of the enzyme with other hydroxylases reveals regions that are conserved among aromatic flavoprotein hydroxylases.
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unusual mechanism of oxygen atom transfer and product rearrangement in the catalytic reaction of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Biochemistry, 1997Co-Authors: Pimchai Chaiyen, Pierre Brissette, David P Ballou, Vincent MasseyAbstract:The oxygenation reaction of 2-methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase with the substrate, MHPC, was investigated. Two oxygenated flavin intermediates C(4a)-hydroperoxy flavin and C(4a)-hydroxy flavin were found, implying that the enzyme functions similarly to flavoprotein hydroxylases. This finding is supported by the results of independent oxygen-18 tracer experiments, which showed that one atom of oxygen from 18O2 and one atom of oxygen from H218O are incorporated in the product. MHPC oxygenase normally catalyzes both the oxygenation and the hydrolytic ring opening of the pyridine ring of MHPC to yield the acyclic compound, alpha-(N-acetylaminomethylene)succinic acid. Using 5-hydroxynicotinic acid (5HN), which has no 2-methyl group, we tested whether the hydrolytic reaction was due to the presence of the 2-methyl group on MHPC (that prevented rearomatization of the initial product) or to the specific properties of MHPC oxygenase. Product analysis of the enzymatic reaction of 5HN and MHPC oxygenase shows that the enzyme catalyzes the hydroxylation and subsequent hydrolysis of the hydroxylated substrate to yield an acyclic product. The investigation of the oxygenation reaction demonstrates that the enzyme uses the same mechanism to catalyze the 5HN reaction as it does in the MHPC reaction.
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thermodynamics and reduction kinetics properties of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Biochemistry, 1997Co-Authors: Pimchai Chaiyen, Pierre Brissette, David P Ballou, Vincent MasseyAbstract:The investigation by absorbance and fluorescence rapid reaction spectrophotometry of the binding of the substrate MHPC (2-methyl-3-Hydroxypyridine-5-carboxylic acid) or the substrate analog 5HN (5-hydroxynicotinic acid) to the flavoprotein MHPCO (2-methyl-3-Hydroxypyridine-5-carboxylic acid oxygenase) shows that the binding proceeds in two steps. An enzyme−substrate complex initially formed is followed by a ligand-induced isomerization. This binding process is required for efficient reduction of the enzyme-bound flavin, as evidenced by the fact that MHPCO−substrate complexes can be reduced by NADH much faster than the enzyme alone. Since redox potential values of MHPCO and MHPCO−substrate complexes are the same, steric factors, such as the relative orientation of MHPC to the enzyme-bound flavin, are important for efficient hydride transfer to occur.
Pimchai Chaiyen - One of the best experts on this subject based on the ideXlab platform.
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selectivity of substrate binding and ionization of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
FEBS Journal, 2015Co-Authors: Thikumporn Luanloet, Jeerus Sucharitakul, Pimchai ChaiyenAbstract:2-Methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (EC 1.14.12.4) from Pseudomonas sp. MA-1 is a flavin-dependent monooxygenase that catalyzes a hydroxylation and aromatic ring cleavage reaction. The functional roles of two residues, Tyr223 and Tyr82, located ~ 5 A away from MHPC, were characterized using site-directed mutagenesis, along with ligand binding, product analysis and transient kinetic experiments. Mutation of Tyr223 resulted in enzyme variants that were impaired in their hydroxylation activity and had Kd values for substrate binding 5-10-fold greater than the wild-type enzyme. Because this residue is adjacent to the water molecule that is located next to the 3-hydroxy group of MHPC, the results indicate that the interaction between Tyr223, H2 O and the 3-hydroxyl group of MHPC are important for substrate binding and hydroxylation. By contrast, the Kd for substrate binding of Tyr82His and Tyr82Phe variants were similar to that of the wild-type enzyme. However, only ~ 40-50% of the substrate was hydroxylated in the reactions of both variants, whereas most of the substrate was hydroxylated in the wild-type enzyme reaction. In free solution, MHPC or 5-hydroxynicotinic acid exists in a mixture of monoanionic and tripolar ionic forms, whereas only the tripolar ionic form binds to the wild-type enzyme. The binding of tripolar ionic MHPC would allow efficient hydroxylation through an electrophilic aromatic substitution mechanism. For the Tyr82His and Tyr82Phe variants, both forms of substrates can bind to the enzymes, indicating that the mutation at Tyr82 abolished the selectivity of the enzyme towards the tripolar ionic form. Transient kinetic studies indicated that the hydroxylation rate constants of both Tyr82 variants are approximately two- to 2.5-fold higher than that of the wild-type enzyme. Altogether, our findings suggest that Tyr82 is important for the binding selectivity of MHPC oxygenase towards the tripolar ionic species, whereas the interaction between Tyr223 and the substrate is important for ensuring hydroxylation. These results highlight how the active site of a flavoenzyme is able to deal with the presence of multiple forms of a substrate in solution and ensure efficient hydroxylation.
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use of 8 substituted fad analogues to investigate the hydroxylation mechanism of the flavoprotein 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Biochemistry, 2004Co-Authors: Pimchai Chaiyen, Vincent Massey, Jeerus Sucharitakul, Jisnuson Svasti, Barrie Entsch, David P BallouAbstract:2-Methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (MHPCO) is a flavoprotein that catalyzes the oxygenation of MHPC to form α-(N-acetylaminomethylene)-succinic acid. Although formally similar to the oxygenation reactions catalyzed by phenol hydroxylases, MHPCO catalyzes the oxygenation of a pyridyl derivative rather than a simple phenol. Therefore, in this study, the mechanism of the reaction was investigated by replacing the natural cofactor FAD with FAD analogues having various substituents (−Cl, −CN, −NH2, −OCH3) at the C8-position of the isoalloxazine. Thermodynamic and catalytic properties of the reconstituted enzyme were investigated and found to be similar to those of the native enzyme, validating that these FAD analogues are reasonable to be used as mechanistic probes. Dissociation constants for the binding of MHPC or the substrate analogue 5-hydroxynicotinate (5HN) to the reconstituted enzymes indicate that the reconstituted enzymes bind well with ligands. Redox potential values of the...
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reaction of 2 methyl 3 Hydroxypyridine 5 carboxylic acid mhpc oxygenase with n methyl 5 hydroxynicotinic acid studies on the mode of binding and protonation status of the substrate
Biochemistry, 1997Co-Authors: Pimchai Chaiyen, Pierre Brissette, David P Ballou, Vincent MasseyAbstract:Titrations of 2-methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase with the substrate MHPC identified the MHPC species bound to the enzyme as the tripolar ionic species. This result was supported by studies of the binding to the enzyme of N-methyl-5-hydroxynicotinic acid (NMHN), an MHPC analog existing only in the tripolar ionic form. The Kd is 55 μM compared to a Kd of 9.2 μM for MHPC and 5.2 μM for 5-hydroxynicotinic acid. Kinetics studies of the binding of NMHN to MHPC oxygenase show that its binding, like that for MHPC and for 5HN, is also a two-step process. Since NMHN never exists as an anionic form, neither of the observed steps is due to the binding of an anionic species as an intermediate step. Investigations of the reduction and oxygenation half reactions demonstrate that the mechanism of catalysis with NMHN is basically the same as with MHPC or with 5-hydroxynicotinic acid. Product analysis from reactions using NMHN, a compound that possesses positive charge on the nitrogen atom, indic...
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gene cloning sequence analysis and expression of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Pimchai Chaiyen, David P Ballou, Vincent MasseyAbstract:The gene encoding 2-methyl-3-Hydroxypyridine-5-carboxylic acid oxygenase (MHPCO; EC 1.14.12.4) was cloned by using an oligonucleotide probe corresponding to the N terminus of the enzyme to screen a DNA library of Pseudomonas sp. MA-1. The gene encodes for a protein of 379 amino acid residues corresponding to a molecular mass of 41.7 kDa, the same as that previously estimated for MHPCO. MHPCO was expressed in Escherichia coli and found to have the same properties as the native enzyme from Pseudomonas sp. MA-1. This study shows that MHPCO is a homotetrameric protein with one flavin adenine dinucleotide bound per subunit. Sequence comparison of the enzyme with other hydroxylases reveals regions that are conserved among aromatic flavoprotein hydroxylases.
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unusual mechanism of oxygen atom transfer and product rearrangement in the catalytic reaction of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Biochemistry, 1997Co-Authors: Pimchai Chaiyen, Pierre Brissette, David P Ballou, Vincent MasseyAbstract:The oxygenation reaction of 2-methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase with the substrate, MHPC, was investigated. Two oxygenated flavin intermediates C(4a)-hydroperoxy flavin and C(4a)-hydroxy flavin were found, implying that the enzyme functions similarly to flavoprotein hydroxylases. This finding is supported by the results of independent oxygen-18 tracer experiments, which showed that one atom of oxygen from 18O2 and one atom of oxygen from H218O are incorporated in the product. MHPC oxygenase normally catalyzes both the oxygenation and the hydrolytic ring opening of the pyridine ring of MHPC to yield the acyclic compound, alpha-(N-acetylaminomethylene)succinic acid. Using 5-hydroxynicotinic acid (5HN), which has no 2-methyl group, we tested whether the hydrolytic reaction was due to the presence of the 2-methyl group on MHPC (that prevented rearomatization of the initial product) or to the specific properties of MHPC oxygenase. Product analysis of the enzymatic reaction of 5HN and MHPC oxygenase shows that the enzyme catalyzes the hydroxylation and subsequent hydrolysis of the hydroxylated substrate to yield an acyclic product. The investigation of the oxygenation reaction demonstrates that the enzyme uses the same mechanism to catalyze the 5HN reaction as it does in the MHPC reaction.
David P Ballou - One of the best experts on this subject based on the ideXlab platform.
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use of 8 substituted fad analogues to investigate the hydroxylation mechanism of the flavoprotein 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Biochemistry, 2004Co-Authors: Pimchai Chaiyen, Vincent Massey, Jeerus Sucharitakul, Jisnuson Svasti, Barrie Entsch, David P BallouAbstract:2-Methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (MHPCO) is a flavoprotein that catalyzes the oxygenation of MHPC to form α-(N-acetylaminomethylene)-succinic acid. Although formally similar to the oxygenation reactions catalyzed by phenol hydroxylases, MHPCO catalyzes the oxygenation of a pyridyl derivative rather than a simple phenol. Therefore, in this study, the mechanism of the reaction was investigated by replacing the natural cofactor FAD with FAD analogues having various substituents (−Cl, −CN, −NH2, −OCH3) at the C8-position of the isoalloxazine. Thermodynamic and catalytic properties of the reconstituted enzyme were investigated and found to be similar to those of the native enzyme, validating that these FAD analogues are reasonable to be used as mechanistic probes. Dissociation constants for the binding of MHPC or the substrate analogue 5-hydroxynicotinate (5HN) to the reconstituted enzymes indicate that the reconstituted enzymes bind well with ligands. Redox potential values of the...
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reaction of 2 methyl 3 Hydroxypyridine 5 carboxylic acid mhpc oxygenase with n methyl 5 hydroxynicotinic acid studies on the mode of binding and protonation status of the substrate
Biochemistry, 1997Co-Authors: Pimchai Chaiyen, Pierre Brissette, David P Ballou, Vincent MasseyAbstract:Titrations of 2-methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase with the substrate MHPC identified the MHPC species bound to the enzyme as the tripolar ionic species. This result was supported by studies of the binding to the enzyme of N-methyl-5-hydroxynicotinic acid (NMHN), an MHPC analog existing only in the tripolar ionic form. The Kd is 55 μM compared to a Kd of 9.2 μM for MHPC and 5.2 μM for 5-hydroxynicotinic acid. Kinetics studies of the binding of NMHN to MHPC oxygenase show that its binding, like that for MHPC and for 5HN, is also a two-step process. Since NMHN never exists as an anionic form, neither of the observed steps is due to the binding of an anionic species as an intermediate step. Investigations of the reduction and oxygenation half reactions demonstrate that the mechanism of catalysis with NMHN is basically the same as with MHPC or with 5-hydroxynicotinic acid. Product analysis from reactions using NMHN, a compound that possesses positive charge on the nitrogen atom, indic...
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gene cloning sequence analysis and expression of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Pimchai Chaiyen, David P Ballou, Vincent MasseyAbstract:The gene encoding 2-methyl-3-Hydroxypyridine-5-carboxylic acid oxygenase (MHPCO; EC 1.14.12.4) was cloned by using an oligonucleotide probe corresponding to the N terminus of the enzyme to screen a DNA library of Pseudomonas sp. MA-1. The gene encodes for a protein of 379 amino acid residues corresponding to a molecular mass of 41.7 kDa, the same as that previously estimated for MHPCO. MHPCO was expressed in Escherichia coli and found to have the same properties as the native enzyme from Pseudomonas sp. MA-1. This study shows that MHPCO is a homotetrameric protein with one flavin adenine dinucleotide bound per subunit. Sequence comparison of the enzyme with other hydroxylases reveals regions that are conserved among aromatic flavoprotein hydroxylases.
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unusual mechanism of oxygen atom transfer and product rearrangement in the catalytic reaction of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Biochemistry, 1997Co-Authors: Pimchai Chaiyen, Pierre Brissette, David P Ballou, Vincent MasseyAbstract:The oxygenation reaction of 2-methyl-3-Hydroxypyridine-5-carboxylic acid (MHPC) oxygenase with the substrate, MHPC, was investigated. Two oxygenated flavin intermediates C(4a)-hydroperoxy flavin and C(4a)-hydroxy flavin were found, implying that the enzyme functions similarly to flavoprotein hydroxylases. This finding is supported by the results of independent oxygen-18 tracer experiments, which showed that one atom of oxygen from 18O2 and one atom of oxygen from H218O are incorporated in the product. MHPC oxygenase normally catalyzes both the oxygenation and the hydrolytic ring opening of the pyridine ring of MHPC to yield the acyclic compound, alpha-(N-acetylaminomethylene)succinic acid. Using 5-hydroxynicotinic acid (5HN), which has no 2-methyl group, we tested whether the hydrolytic reaction was due to the presence of the 2-methyl group on MHPC (that prevented rearomatization of the initial product) or to the specific properties of MHPC oxygenase. Product analysis of the enzymatic reaction of 5HN and MHPC oxygenase shows that the enzyme catalyzes the hydroxylation and subsequent hydrolysis of the hydroxylated substrate to yield an acyclic product. The investigation of the oxygenation reaction demonstrates that the enzyme uses the same mechanism to catalyze the 5HN reaction as it does in the MHPC reaction.
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thermodynamics and reduction kinetics properties of 2 methyl 3 Hydroxypyridine 5 carboxylic acid oxygenase
Biochemistry, 1997Co-Authors: Pimchai Chaiyen, Pierre Brissette, David P Ballou, Vincent MasseyAbstract:The investigation by absorbance and fluorescence rapid reaction spectrophotometry of the binding of the substrate MHPC (2-methyl-3-Hydroxypyridine-5-carboxylic acid) or the substrate analog 5HN (5-hydroxynicotinic acid) to the flavoprotein MHPCO (2-methyl-3-Hydroxypyridine-5-carboxylic acid oxygenase) shows that the binding proceeds in two steps. An enzyme−substrate complex initially formed is followed by a ligand-induced isomerization. This binding process is required for efficient reduction of the enzyme-bound flavin, as evidenced by the fact that MHPCO−substrate complexes can be reduced by NADH much faster than the enzyme alone. Since redox potential values of MHPCO and MHPCO−substrate complexes are the same, steric factors, such as the relative orientation of MHPC to the enzyme-bound flavin, are important for efficient hydride transfer to occur.
Philip Beale - One of the best experts on this subject based on the ideXlab platform.
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Studies on the activity of three palladium(II) compounds of the form: trans-PdL2Cl2 where L=2-Hydroxypyridine, 3-Hydroxypyridine, and 4-Hydroxypyridine.
Journal of inorganic biochemistry, 2006Co-Authors: Fazlul Huq, Hasan Tayyem, Philip BealeAbstract:Abstract Three planaraminepalladium(II) complexes of the form: trans -PdCl 2 L 2 , code named TH5, TH6 and TH7 where L = 3-Hydroxypyridine, 2-Hydroxypyridine and 4-Hydroxypyridine respectively have been investigated for antitumour activity against ovarian cancer cell lines: A2780, A2780 cisR and A2780 ZD0473R . Although the compounds are generally found to be less active than cisplatin, they are often found to be more active against the resistant cell lines than the parent cell line. Among TH5, TH6 and TH7, TH6 which has two 2-Hydroxypyridine non-labile ligands is found to be most active against the three cell lines. Variations in activity of TH5, TH6 and TH7 indicate that non-covalent interactions may be playing a significant role in activity. In particular, the results indicate that small changes in planaramine ligands such as the position of the polar OH group can have a more profound effect on activity of the compounds. Palladium compounds are generally found to be toxic rather tumour active because of much higher reactivity. Low but significant activity of trans -palladium(II) complexes TH5, TH6 and TH7 against the ovarian cancer cell lines indicates that it is believed to be associated with the decrease in their reactivity due to the presence of two sterically hindered planaramine ligands.
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studies on the synthesis characterization binding with dna and activities of two cis planaramineplatinum ii complexes of the form cis ptl nh3 cl2 where l 3 Hydroxypyridine and 2 3 diaminopyridine
BMC Chemical Biology, 2006Co-Authors: Ahmed Abdullah, Philip Beale, Hasan Tayyem, Ashraf Chowdhury, Keith FisherAbstract:Cis-planaramineplatinum(II) complexes like their trans isomers are often found to be active against cancer cell lines. The present study deals with the synthesis, characterization and determination of activity of new cis-planaramineplatinum(II) complexes. Two cis-planaramineplatinum(II) complexes: cis-(3-Hydroxypyridine)(ammine)dichloroplatinum(II) (code named AH3) and cis-(2,3-diaminopyridine)(ammine)dichloroplatinum(II) (code named AH7) have been prepared and characterised based on elemental analyses, IR, Raman, mass and 1H NMR spectral measurements. The interactions of the compounds with pBR322 plasmid DNA have been investigated and their activity against ovarian cancer cell lines: A2780, A2780cisR and A2780ZD047Rhave been determined. Like cisplatin, AH3 and AH7 are believed to form mainly monofunctional N7(G) and bifunctional intrastrand N7(G)N7(G) adducts with DNA, causing a local distortion of a DNA strand. As a result, gel mobility of the DNA changes. Both AH3 and AH7 are found to be less active than cisplatin against the three cell lines with AH3 being the more active compound of the two. The higher activity of AH3 is in line with its lower molar conductivity value corresponding to a lower degree of dissociation. The differences in activity of AH3, AH7 and cisplatin against the cell lines illustrate structure-activity relationship.
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Synthesis, characterization and binding with DNA of four planaramineplatinum(II) complexes of the forms : trans-PtL2Cl2 and [PtL3Cl]Cl, where L = 3-Hydroxypyridine, 4-Hydroxypyridine and imidazo(1,2-α)pyridine
Journal of inorganic biochemistry, 2005Co-Authors: Mohammad Ashraf Chowdhury, Fazlul Huq, Philip Beale, Ahmed Abdullah, Keith FisherAbstract:Four new trans-planaramineplatinum(II) complexes, three of the form: trans-PtCl2L2, code named CH1, CH2 and CH4 where L = 3-Hydroxypyridine, 4-Hydroxypyridine and imidazo[1,2-α]pyridine, respectively, and one of the form: PtClL3, code named CH3 where L = 3-Hydroxypyridine, have been prepared and characterized by elemental analyses and IR, Raman, mass and 1H NMR spectral studies. The interactions of the compounds with salmon sperm and pBR322 plasmid DNAs have been investigated and their activity against human ovarian cancer cell lines: A2780, A2780cisR and A2780ZD0473R have also been determined. The compounds are believed to form mainly monofunctional N7(G) and bifunctional intrastrand N7(G)N7(G) adducts with DNA, causing a local distortion of DNA as a result of which gel mobility of the DNA changes. The compound containing three planaramine ligands per molecule (CH3) is found to be less reactive than the compounds containing two planaramine ligands per molecule (CH1, CH2 and CH4), which in turn are less reactive than compounds containing one of the same planaramine ligands per molecule. The decrease in reactivity is reflected in lower molar conductivity values (indicating lower degree of dissociation), less pronounced changes caused to DNA conformation (indicating decreased level of platinum–DNA binding) and lower activity. The decreased reactivity of the compounds is due to a greater steric crowding produced by the bulky planaramine ligands. Changes in DNA conformation are also found to be a function of the actual nature of the planaramine ligand. The results illustrate structure–activity relationship.
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studies on activities cell uptake and dna binding of four trans planaramineplatinum ii complexes of the form trans ptl nh3 cl2 where l 2 Hydroxypyridine imidazole 3 Hydroxypyridine and imidazo 1 2 α pyridine
Journal of Inorganic Biochemistry, 2004Co-Authors: Jun Qing Yu, Hassan Daghriri, Philip BealeAbstract:Four trans-planaramineplatinum(II) complexes code named YH9, YH10, YH11 and YH12 each of the form trans-PtL(NH3)Cl2, where L=2-Hydroxypyridine and 3-Hydroxypyridine, imidazole, and imidazo(1,2-α)pyridine for YH9, YH10, YH11 and YH12, respectively, have been synthesized and the activity of the compounds against human cancer cell lines, cell uptake, DNA-binding and nature of interaction with pBR322 plasmid DNA have been studied. The compound having imidazo(1,2-α)pyridine ligand as one the carrier ligands in the trans-configuration is found to be significantly more active than cis-platin against ovarian A2780cisR cancer cell line corresponding with higher Pt-DNA binding. All other compounds have resistance factors less than that for cis-platin in the A2780 and A2780cisR cell lines. A greater prevention of BamH1 digestion with increasing concentration of the compounds indicates that as the compounds bind with nucleobases in DNA, the DNA conformation is changed sufficiently so as to prevent BamH1 digestion at the specific GG site. Gel electrophoresis results also indicate that as the compounds bind to DNA, unwinding of supercoiled form I DNA takes place to change it from the negatively supercoiled form I through relaxed circular form I to the positively supercoiled form I.
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Studies on the synthesis and characterization of four trans-planaramineplatinum(II) complexes of the form trans-PtL(NH3)CL2 where L = 2-Hydroxypyridine, 3-Hydroxypyridine, imidazole, and imidazo(1,2-α)pyridine
European journal of medicinal chemistry, 2004Co-Authors: Fazlul Huq, Hassan Daghriri, Philip Beale, Keith FisherAbstract:Abstract Four trans-planaramineplatinum(II) complexes code named YH9, YH10, YH11 and YH12, each of the form trans-PtL(NH3)Cl2 where L = 2-Hydroxypyridine and 3-Hydroxypyridine, imidazole, and imidazo(1,2-α)pyridine for YH9, YH10, YH11 and YH12, respectively. All of the compounds have significant anticancer activity against human cancer cell lines. YH12 is found to be significantly more active than cisplatin against cisplatin-resistant ovary cell line A2780cisR.
Keith Fisher - One of the best experts on this subject based on the ideXlab platform.
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studies on the synthesis characterization binding with dna and activities of two cis planaramineplatinum ii complexes of the form cis ptl nh3 cl2 where l 3 Hydroxypyridine and 2 3 diaminopyridine
BMC Chemical Biology, 2006Co-Authors: Ahmed Abdullah, Philip Beale, Hasan Tayyem, Ashraf Chowdhury, Keith FisherAbstract:Cis-planaramineplatinum(II) complexes like their trans isomers are often found to be active against cancer cell lines. The present study deals with the synthesis, characterization and determination of activity of new cis-planaramineplatinum(II) complexes. Two cis-planaramineplatinum(II) complexes: cis-(3-Hydroxypyridine)(ammine)dichloroplatinum(II) (code named AH3) and cis-(2,3-diaminopyridine)(ammine)dichloroplatinum(II) (code named AH7) have been prepared and characterised based on elemental analyses, IR, Raman, mass and 1H NMR spectral measurements. The interactions of the compounds with pBR322 plasmid DNA have been investigated and their activity against ovarian cancer cell lines: A2780, A2780cisR and A2780ZD047Rhave been determined. Like cisplatin, AH3 and AH7 are believed to form mainly monofunctional N7(G) and bifunctional intrastrand N7(G)N7(G) adducts with DNA, causing a local distortion of a DNA strand. As a result, gel mobility of the DNA changes. Both AH3 and AH7 are found to be less active than cisplatin against the three cell lines with AH3 being the more active compound of the two. The higher activity of AH3 is in line with its lower molar conductivity value corresponding to a lower degree of dissociation. The differences in activity of AH3, AH7 and cisplatin against the cell lines illustrate structure-activity relationship.
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Synthesis, characterization and binding with DNA of four planaramineplatinum(II) complexes of the forms : trans-PtL2Cl2 and [PtL3Cl]Cl, where L = 3-Hydroxypyridine, 4-Hydroxypyridine and imidazo(1,2-α)pyridine
Journal of inorganic biochemistry, 2005Co-Authors: Mohammad Ashraf Chowdhury, Fazlul Huq, Philip Beale, Ahmed Abdullah, Keith FisherAbstract:Four new trans-planaramineplatinum(II) complexes, three of the form: trans-PtCl2L2, code named CH1, CH2 and CH4 where L = 3-Hydroxypyridine, 4-Hydroxypyridine and imidazo[1,2-α]pyridine, respectively, and one of the form: PtClL3, code named CH3 where L = 3-Hydroxypyridine, have been prepared and characterized by elemental analyses and IR, Raman, mass and 1H NMR spectral studies. The interactions of the compounds with salmon sperm and pBR322 plasmid DNAs have been investigated and their activity against human ovarian cancer cell lines: A2780, A2780cisR and A2780ZD0473R have also been determined. The compounds are believed to form mainly monofunctional N7(G) and bifunctional intrastrand N7(G)N7(G) adducts with DNA, causing a local distortion of DNA as a result of which gel mobility of the DNA changes. The compound containing three planaramine ligands per molecule (CH3) is found to be less reactive than the compounds containing two planaramine ligands per molecule (CH1, CH2 and CH4), which in turn are less reactive than compounds containing one of the same planaramine ligands per molecule. The decrease in reactivity is reflected in lower molar conductivity values (indicating lower degree of dissociation), less pronounced changes caused to DNA conformation (indicating decreased level of platinum–DNA binding) and lower activity. The decreased reactivity of the compounds is due to a greater steric crowding produced by the bulky planaramine ligands. Changes in DNA conformation are also found to be a function of the actual nature of the planaramine ligand. The results illustrate structure–activity relationship.
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Studies on the synthesis and characterization of four trans-planaramineplatinum(II) complexes of the form trans-PtL(NH3)CL2 where L = 2-Hydroxypyridine, 3-Hydroxypyridine, imidazole, and imidazo(1,2-α)pyridine
European journal of medicinal chemistry, 2004Co-Authors: Fazlul Huq, Hassan Daghriri, Philip Beale, Keith FisherAbstract:Abstract Four trans-planaramineplatinum(II) complexes code named YH9, YH10, YH11 and YH12, each of the form trans-PtL(NH3)Cl2 where L = 2-Hydroxypyridine and 3-Hydroxypyridine, imidazole, and imidazo(1,2-α)pyridine for YH9, YH10, YH11 and YH12, respectively. All of the compounds have significant anticancer activity against human cancer cell lines. YH12 is found to be significantly more active than cisplatin against cisplatin-resistant ovary cell line A2780cisR.
