Kin Y Tam

City University of Macau, Macao, Macau, Macao

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Publications (56)226.81 Total impact

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    ABSTRACT: The extent of ionization of a drug molecule at different pH values can be characterized by its pKa (acid dissociation constants). It is an important parameter in pharmaceutical development to rationalize the physiochemical and biopharmaceutical properties of the drug molecule. UV titration for pKa determination is one of the popular methods. The success of this method requires the molecule exhibiting strong pH-dependent spectral shift related to the ionization process. Depending on the proximity between the ionizable group and the chromophore, the spectral shift may not be strong enough to warrant a successful determination. In a previous study, it has been reported that a distance of three σ bonds between the chromophore and the ionizable group was the limit for a precise pKa determination. In this work, a UV titration method for pKa determination, with a particular emphasis on molecules with weak pH-dependent spectral shift is investigated. It has been shown that the pKa values determined from this study are in good agreement with those determined using potentiometric method and literature data (R(2)=0.998). Our methodology revealed that successful pKa determination is feasible even with a separation distance of five σ bonds between the chromophore and the ionizable group. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of pharmaceutical and biomedical analysis 10/2015; 114. DOI:10.1016/j.jpba.2015.05.009 · 2.98 Impact Factor
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    Xiaoli Wu · Jing Li · Wei Zhou · Kin Tam ·

    09/2015; 3(3). DOI:10.5599/admet.3.3.195
  • Jing Li · Wei Zhou · Xiaoli Wu · Kin Tam ·

    09/2015; 3(3). DOI:10.5599/admet.3.3.194
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    Shao-Lin Zhang · Xiaohui Hu · Wen Zhang · Huankai Yao · Kin Yip Tam ·
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    ABSTRACT: Many cancer cells demonstrate a high rate of glucose consumption via glycolysis to provide intermediates for macromolecule biosynthesis. To accomplish this metabolic change, the expression of pyruvate dehydrogenase kinases (PDKs) is rapidly increased in cancer cells. Inhibition of PDKs could promote the function of mitochondria by increasing the oxidative metabolism of pyruvate, resulting in the death of cancer cells. In this review, we provide an overview of the structural information available for PDKs and their connections to known therapeutic effects. We then describe the development of small molecule PDK inhibitors in medicinal chemistry with particular emphasis as anticancer agents. Finally, directions for further development of PDK inhibitors as potential anticancer agents are discussed. Copyright © 2015. Published by Elsevier Ltd.
    Drug discovery today 04/2015; 20(9). DOI:10.1016/j.drudis.2015.03.012 · 6.69 Impact Factor
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    ABSTRACT: The current study aims to investigate the pharmacokinetics of multi-components (caffeic acid, quinic acid, genistein, luteolin, quercetin, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, arctigenin, genistin, luteoloside, astragalin, hyperoside, isoquercitrin, 3,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, rutin, loganin, pinoresinol-β-d-glucoside, phillyrin, isoforsythoside, forsythoside A and forsythoside B) following oral administration of Flos Lonicerae Japonicae-Fructus Forsythiae herb couple in rats. A rapid and sensitive UPLC-ESI-MS/MS with sequential positive and negative ionization modes was developed to determine the 23 absorbed ingredients using one sample preparation combined with three chromatographic conditions in rat plasma. After mixing with internal standard (IS) (tinidazole and chloramphenicol), samples were pretreated by liquid-liquid extraction (LLE) with n-butyl alcohol/ethyl acetate (1:1, v/v). The separations for pinoresinol-β-d-glucoside, phillyrin, isoforsythoside, forsythoside A and forsythoside B were performed on an ACQUITY UPLC BEH C18 column (100mm×2.1mm, 1.7μm) with acetonitrile/methanol (4:1, v/v)-water as mobile phase. For analyzing quinic acid, an ACQUITY UPLC HSS T3 column (100mm×2.1mm, 1.8μm) was applied with acetonitrile/methanol (4:1, v/v)-0.01% formic acid as mobile phase after dilution up to 25-fold. The same column was applied to the other components with acetonitrile/methanol (4:1, v/v)-0.4% formic acid as mobile phase. The method validation results demonstrated that the proposed method was sensitive, specific and reliable, which was successfully applied to the pharmacokinetic study of the multi-components after oral administration of Flos Lonicerae Japonicae-Fructus Forsythiae herb couple. Copyright © 2014 Elsevier B.V. All rights reserved.
    Journal of Chromatography A 12/2014; 1376. DOI:10.1016/j.chroma.2014.12.018 · 4.17 Impact Factor
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    Shao-Lin Zhang · Huankai Yao · Chenyin Wang · Kin Y. Tam ·
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    ABSTRACT: Binding affinities of fluconazole and its analogue 2-(2,4-dichlorophenyl)-1,3-di(1H-1,2,4-triazol-yl)-2-propanol (DTP) to human serum albumin (HSA) were investigated under approximately human physiological conditions. The obtained result indicated that HSA could generate fluorescent quenching by fluconazole and DTP because of the formation of non-fluorescent ground-state complexes. Binding parameters calculated from the Stern-Volmer and the Scatchard equations showed that fluconazole and DTP bind to HSA with binding affinities of the order 10(4)L/mol. The thermodynamic parameters revealed that the binding was characterized by negative enthalpy and positive entropy changes, suggesting that the binding reaction was exothermic. Hydrogen bonds and hydrophobic interaction were found to be the predominant intermolecular forces stabilizing the drug-protein. The effect of metal ions on the binding constants of fluconazole-HSA complex suggested that the presence of Mg(2+) and Zn(2+) ions could decrease the free drug level and extend the half-life in the systematic circulation. Docking experiments revealed that fluconazole and DTP binds in HSA mainly by hydrophobic interaction with the possibility of hydrogen bonds formation between the drugs and the residues Arg 222, Lys 199 and Lys 195 in HSA.
    Bioorganic & Medicinal Chemistry Letters 09/2014; 24(21). DOI:10.1016/j.bmcl.2014.09.034 · 2.42 Impact Factor
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    Wen Zhang · Chenyin Wang · Kin Y Tam ·
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    ABSTRACT: The objective of this study is to evaluate whether the accumulation model developed by Zarfl et al. (2008) could be used to predict the minimal inhibitory concentration (MIC) of a group of antibacterial fluoroquinolones (FQs) for Escherichia coli (E. coli). Our model, which is based on the "Fick-Nernst-Planck" equation and the permeability of the neutral and charged species as well as the physicochemical parameters of the FQs, could predict 1/MIC90 using a linear function. It is envisaged that in the drug development projects of new FQs, the accumulation model described in this study could be utilized as an effective tool to enable early assessment of MIC value using physiochemical parameters.
    Bio-medical materials and engineering 09/2014; 24(6):3745-51. DOI:10.3233/BME-141203 · 1.09 Impact Factor
  • Chenyin Wang · Alex Avdeef · Wen Zhang · Kin Y Tam ·
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    ABSTRACT: The purpose of this study is to predict human jejunal permeability (Peff) and fraction absorbed in human (%Fa) for a group of antibacterial fluoroquinolones (FQs), by using a biophysical model based on measured Caco-2 permeability. The predicted Peff (in 10-4cm·s-1 units) ranged from 0.7 (norfloxacin) to 4.5 (pefloxacin). The calculated %Fa for norfloxacin = 51% (lit. 35%) and for ciprofloxacin = 76% (lit. 81%). Most of the FQs showed calculated %Fa>90%, and are expected to be well-absorbed. Estimates of Peff can be predicted by the biophysical model. From these values, the human absorption may be calculated. Where absorption comparisons were possible, the agreement was acceptably good.
    Bio-medical materials and engineering 09/2014; 24(6):3849-54. DOI:10.3233/BME-141215 · 1.09 Impact Factor
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    ABSTRACT: In this review, we will briefly outline the voltammetric investigations of the transfer of ionisable drugs at the interface between two immiscible electrolyte solutions. The voltammetric techniques enable the determination of some key in vitro properties of ionisable drugs, including partition coefficient, diffusion coefficient and membrane permeability. Some successful applications will be highlighted, together with the background methodologies.
    02/2014; 2(3):143-156. DOI:10.5599/admet.2.3.22
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    Matej Velicky · Kin Y Tam · Robert A.W. Dryfe ·
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    ABSTRACT: A polarization study carried out on a thin supported liquid membrane separating two aqueous compartments is presented. Transfer of both the ionized and uncharged form of an organic tracer dye, rhodamine B ([9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene]-diethylammonium chloride), across supported liquid membranes composed of one of 1-octanol (octan-1-ol), 1,9-decadiene (deca-1,9-diene), 1,2-dichlorobenzene or nitrophenyl octyl ether (1-(2-nitrophenoxy)octane), was studied using cyclic voltammetry and UV-vis absorption spectrophotometry. Concentration analysis indicates that the high membrane concentration of rhodamine B determines the ionic transfer observed via voltammetry, which is consistent with the low aqueous ionic concentration and large membrane/aqueous distribution of the molecule. The observed double-transfer voltammogram, although it has been largely neglected in previous literature, is a logical consequence of the presence of two liquid-liquid interfaces and is rationalised in terms of ion transfer across the two interfaces on either side of the membrane and supported by voltammograms obtained for a series of ions of varied lipophilicity. The bipolar nature of the voltammetric response offers an effective way of mass transport control via changing polarity of the applied voltage and finds immediate use in extraction, purification and separation applications.
    Analytical Chemistry 12/2013; 86(1). DOI:10.1021/ac402328w · 5.64 Impact Factor

  • Cancer Research 08/2013; 73(8 Supplement):2348-2348. DOI:10.1158/1538-7445.AM2013-2348 · 9.33 Impact Factor
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    ABSTRACT: ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonyl-morpholino-pyrimidines which show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in-vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in-vivo.
    Journal of Medicinal Chemistry 02/2013; 56(5). DOI:10.1021/jm301859s · 5.45 Impact Factor
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    ABSTRACT: The purpose of this study is to develop a droplet-based microfluidic device capable of monitoring drug precipitation upon a shift from gastric pH (pH 1.5) to intestinal pH (pH 6.5-7.0). The extent of precipitation occurring in droplets over time was measured using a novel on-chip laser scattering technique specifically developed for this study. The precipitation of ketoconazole, a poorly water-soluble basic drug, was investigated under different concentrations and pH values. It has been shown that the drug precipitates rapidly under supersaturation. Two water-soluble aqueous polymers, namely, polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) have been evaluated as precipitation inhibitors. HPMC was shown to be the most potent precipitation inhibitor. It is envisaged that the microfluidic pH-shift method developed in this study would form a proof-of-concept study, towards the development of a high throughput method for screening pharmaceutical excipients/precipitation inhibitors.
    The Analyst 01/2013; 138:339-345. DOI:10.1039/c2an36364j · 4.11 Impact Factor
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    Matěj Velický · Kin Y. Tam · Robert A.W. Dryfe ·
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    ABSTRACT: Liquid/liquid electrochemistry has been used to study the transfer of weakly ionised species across the interface between water and 1,2-dichloroethane. It is shown that while transfer of a fully ionised species can be readily used for determination of its diffusion coefficient, transfer of a partially ionised species, such as many common pharmaceutical agents, involves complex ionisation/distribution behaviour, which invalidates the conventional analysis. As a result, the aqueous diffusion coefficient of the transferred species is underestimated by at least one order of magnitude. An alternative method to study the transfer of partially ionised drug molecules employing a rotating liquid/liquid interface is proposed and reported. The alternative approach, which is based on a previously reported rotating diffusion cell approach, employs a lipophilic membrane that stabilises the liquid/liquid interface and allows stirring. This hydrodynamically controlled configuration was successfully applied to transfer of partially ionised drug species, and expected values of the aqueous diffusion coefficient were obtained.
    Journal of electroanalytical chemistry 09/2012; 683:94–102. DOI:10.1016/j.jelechem.2012.07.037 · 2.73 Impact Factor
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    ABSTRACT: The stepwise hydrogenation of 9-ethylcarbazole to 9-ethyl-perhydrocarbazole (Pl 12[H]) via partially hydrogenated intermediate(s) was studied over a number of supported ruthenium and rhodium catalysts. The reaction pathways were modelled and the rate constants for individual hydrogenation steps were compared. It was found that the selectivities to the reaction intermediates and products were highly dependent on the electronic structure of the particular metal and the nature of the support used. Ruthenium was found to be the most active metal for this reaction but it suffered from a poor selectivity to the desired product due to the formation of a kinetically stable intermediate, 9-ethyl-octahydrocarbazole (Pl 8[H]) in short reaction time. On the other hand, rhodium catalysts with moderate activity gave a higher selectivity to the fully hydrogenated product under comparable conditions. It was also found that the presence of a hydrophilic support such as alumina or rutile can give kinetically favoured cis-isomers of the 9-ethyl-perhydrocarbazole. Regarding application of the reversible hydrogen storage concept, the storage material should be able to switch between fully hydrogen loaded and unloaded forms during hydrogenation (material regeneration) and dehydrogenation (delivery of hydrogen gas) in short times. Formation of any stable intermediates and stereo-non-favoured isomers with a particular type of catalyst can result in significant implications to the overall storage capacity as well as operation times for hydrogen gas delivery and regeneration. Thus, this study yields valuable information on the suitability of various metal catalysts for use in hydrogen storage systems based on the liquid organic hydride (LOH) concept.
    Energy & Environmental Science 08/2012; 5(9):8621-8630. DOI:10.1039/C2EE22066K · 20.52 Impact Factor
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    ABSTRACT: It is demonstrated that engineered arginase with a single protruded site of cysteine deliberately placed away from its active centre by site-directed mutagenesis can facilitate its attachment on a gold-nanoparticle surface with atomic precision, resulting in no apparent loss in enzymatic activity.
    Chemical Communications 07/2012; 48(62):7693-5. DOI:10.1039/c2cc32863a · 6.83 Impact Factor
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    ABSTRACT: The purposes of this study are to evaluate if the PAMPA (Parallel Artificial Membrane Permeability Assay) permeability and the true partition coefficient could be useful for predicting AUC and MIC data of a group of antibacterial fluoroquinolones (FQs). The protonation macro- and microconstants, the n-octanol/water partition coefficients at isoelectric pHs, and the PAMPA permeability of 11 selected FQs were determined, and used to calculate the true partition coefficient, the interactivity parameter between the acidic and basic group, and the apparent intrinsic permeability. It has been shown that the apparent intrinsic permeability correlates well with the AUC in human, whereas the true partition coefficient and the interactivity parameter correlate with 1/MIC values on two Gram-positive bacteria, namely Streptococcus pneumonia and Staphylococcus aureus (methicillin-susceptible). The AUC/MIC ratios predicted from these correlations have shown to be in good agreement with the literature values. It is envisaged that the models described in this study could be useful in the development of new FQs by enabling an early prediction of AUC/MIC ratios based on physicochemical properties.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 05/2012; 47(1):21-7. DOI:10.1016/j.ejps.2012.04.022 · 3.35 Impact Factor
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    Matěj Velický · Kin Y. Tam · Robert A. W. Dryfe ·
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    ABSTRACT: The preparation and application of a simple silver/silver sulfate reference electrode for an aqueous solution, which can be used as an alternative in chloride-free systems, is reported. The electrodes are prepared by galvanostatic oxidation of silver wire in sulfate solution: the potential stability with time is measured as a function of the current density and overall charge used in oxidation. The electrode potential is also measured in a wide concentration range of sulfate and chloride solutions and an explanation of the observed stability is presented. The range of optimal conditions, crucial for the correct electrode operation, is discussed.
    Analytical methods 05/2012; 4(5):1207-1211. DOI:10.1039/C2AY00011C · 1.82 Impact Factor
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    ABSTRACT: The use of liquid organic hydrides (LOH) as a chemical hydrogen store to supply hydrogen gas for a polymer electrolyte membrane fuel cell (PEFC) is explored. In the present work, hydrogenation of 9-ethylcarbazole is particularly investigated in the liquid phase over different unsupported noble metal powders. The kinetics obtained from the hydrogenation of the substrate over these catalytic systems are modeled, and the derived fundamental rate constants are systematically compared. It is found that the differences in activity and product distribution of the reaction over different metal surfaces depend critically on the electronic structures of the metals. From the prospective application of 9-ethyl-carbazole, an effective catalyst should be able to convert the substrate to the fully hydrogenated cis product without forming any kinetically stable intermediates. Ruthenium is the most active catalyst among all the metals studied for this reaction. However, this catalyst suffers from relatively low selectivity with the accumulation of large quantities of partially hydrogenated intermediates due to weak adsorption and poor surface diffusion of the intermediates for further hydrogenation.
    The Journal of Physical Chemistry C 03/2012; 116(13):7421–7429. DOI:10.1021/jp212249g · 4.77 Impact Factor
  • Matěj Velický · Kin Y Tam · Robert A W Dryfe ·
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    ABSTRACT: An analytical technique for the detection of permeation of a fully ionized analyte across a lipophilic membrane is reported. The system, which is comprised of two aqueous compartments (donor and acceptor) separated by a supported liquid membrane, is based on the parallel artificial membrane permeation assay (PAMPA), widely used in the drug discovery process to estimate permeability in vivo. The in situ spectroelectrochemical method developed here employs mechanical stirring of the solution phases on either side of the membrane, external polarization of the membrane, and in situ detection of the analyte via UV-vis spectrophotometry. The flux of the crystal violet cation across the membrane is simultaneously measured via UV-vis spectrophotometry and voltammetry/chronoamperometry as a function of applied potential. The relative contribution of two permeation modes, i.e., that due to naked ions and ion-pairs, is thereby quantified. The open circuit potential difference between the two aqueous compartments and the cyclic voltammetric response are also recorded as a function of time and compared with the predicted values.
    Analytical Chemistry 03/2012; 84(5):2541-7. DOI:10.1021/ac300016n · 5.64 Impact Factor

Publication Stats

1k Citations
226.81 Total Impact Points


  • 2015
    • City University of Macau
      Macao, Macau, Macao
  • 2013-2015
    • University of Macau
      • Faculty of Health Sciences
      Macao, Macau, Macao
  • 2008-2013
    • AstraZeneca
      Tukholma, Stockholm, United Kingdom
  • 2012
    • University of Oxford
      • Department of Chemistry
      Oxford, England, United Kingdom