Timothy J. Hubin

Southwestern Oklahoma State University, Weatherford, Oklahoma, United States

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Publications (41)139.65 Total impact

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    ABSTRACT: The first 2-pyridylmethyl pendant-armed ethylene cross-bridged cyclam ligand has been synthesized and successfully complexed to Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), and Zn(2+) cations. X-ray crystal structures were obtained for all six complexes and demonstrate pentadentate binding of the ligand with the requisite cis-V configuration of the cross-bridged cyclam ring in all cases, leaving a potential labile binding site cis to the pyridine donor for interaction of the complex with oxidants and/or substrates. The electronic properties of the complexes were evaluated using solid-state magnetic moment determination and acetonitrile solution electronic spectroscopy, which both agree with the crystal structure determination of high-spin divalent metal complexes in all cases. Cyclic voltammetry in acetonitrile revealed reversible redox processes in all but the Ni(2+) complex, suggesting that catalytic reactivity involving electron-transfer processes is possible for complexes of this ligand. Kinetic studies of the dissociation of the ligand from the copper(II) complex under strongly acidic conditions and elevated temperatures revealed that the pyridine pendant arm actually destabilizes the complex compared to the parent cross-bridged cyclam complex. Screening for oxidation catalysis using hydrogen peroxide as the terminal oxidant for the most biologically relevant Mn(2+), Fe(2+), and Cu(2+) complexes identified the Mn(2+) complex as a potential mild oxidation catalyst worthy of continued development.
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    ABSTRACT: Novel bisquinoline derivatives of tetraazamacrocyclic compounds, namely 4,10-bis(7-chloroquinoline)-1,4,7,10-tetraazacyclododecane (1, Scheme 1); 4,10-bis(7-chloroquinoline)-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (6, Scheme 2); 4,11-bis(7-chloroquinoline)- 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (6a, Scheme 3) and 4,10-bis(7-chloroquinoline)-1,4,7,10-tetraazabicyclo[5.5.2] tetradecane (6b, Scheme 3) which are potential antimalarial drugs have been synthesized. The macrocycle framework had to be modified to allow attachment of the substituent (4,7-dichloroquinoline) at the nitrogen atom. The initial synthesis of (1) by direct derivatization was inefficient for selective functionalization and consequently the desired product was isolated in low yield. We have found that by choosing N-methylpyrrolidinone as the reaction solvent, with triethylamine as base, and elevating the reaction temperature, product (1) was accessed with yields of up to 45%. Compounds 6, 6a and 6b were synthesized via regioselective modification of the macrocyclic framework before the attachment of the 4,7-dichloroquinoline substituent.
    Current Organic Synthesis 12/2014; 11(6). DOI:10.2174/1570179411666140424232630 · 2.44 Impact Factor
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    ABSTRACT: Available data from different laboratories have confirmed that both Ca(2+) and Cl(-) are crucial for water oxidation in Photosystem II. However, their roles are still elusive. Using a manganese(II) complex having a cross-bridged cyclen ligand as a model, the influence of Ca(2+) on the oxidative reactivity of the manganese(II) complex and its corresponding manganese(IV) analogue were investigated. It has been found that adding Ca(2+) can significantly improve the oxygenation efficiency of the manganese(II) complex in sulfide oxidation and further accelerate the oxidation of sulfoxide to sulfone. Similar improvements have also been observed for Mg(2+), Sr(2+), and Ba(2+). A new monomeric manganese(IV) complex having two cis-hydroxide ligands has also been isolated through oxidation of the corresponding manganese(II) complex with H2O2 in the presence of NH4PF6. This rare cis-dihydroxomanganese(IV) species has been well characterized by X-ray crystallography, electrochemistry, electron paramagnetic resonance, and UV-vis spectroscopy. Notably, using the manganese(IV) complex as a catalyst demonstrates higher activity than the corresponding manganese(II) complex, and adding Ca(2+) further improves its catalytic efficiency. However, adding Cl(-) decreases its catalytic activity. In electrochemical studies of manganese(IV) complexes with no chloride ligand present, adding Ca(2+) positively shifted the redox potential of the Mn(IV)/Mn(III) couple but negatively shifted its Mn(V)/Mn(IV) couple. In the manganese(II) complex having a chloride ligand, adding Ca(2+) shifted both the Mn(IV)/Mn(III) and Mn(V)/Mn(IV) couples in the negative direction. The revealed oxidative reactivity and redox properties of the manganese species affected by Ca(2+) and Cl(-) may provide new clues to understanding their roles in the water oxidation process of Photosystem II.
    Inorganic Chemistry 11/2014; DOI:10.1021/ic501342c · 4.79 Impact Factor
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    ABSTRACT: Lipophilicity, expressed by log P, is an important physicochemical property of drugs that affects many biological processes, including drug absorption and distribution. The main purpose of this study to determine the log P values of newly discovered drug leads using reversed-phase high-performance liquid chromatography (RP-HPLC). The reference standards, with varying polarity ranges, were dissolved in methanol and analyzed by RP-HPLC using a C18 column. The mobile phase consisted of a mixture of acetonitrile, methanol and water in a gradient elution mode. A calibration curve was plotted between the experimental log P values and obtained log k values of the reference standard compounds and a best fit line was obtained. The log k values of the new drug leads were determined in the same solvent system and were used to calculate the respective log P values by using the best fit equation. The log P vs. log k data gave a best fit linear curve that had an R2 of 0.9786 with Pvalues of the intercept and slope of 1.19 x 10(-6) and 1.56 x 10(-10), respectively, at 0.05 level of significance. Log P values of 15 new drug leads and related compounds, all of which are derivatives of macrocyclic polyamines and their metal complexes, were determined. The values obtained are closely related to the calculated log P (Clog P) values using ChemDraw Ultra 12.0. This experiment provided efficient, fast and reasonable estimates of log P values of the new drug leads by using RP-HPLC.
    Biocontrol Science and Technology 09/2014; 69(9):655-62. DOI:10.1691/ph.2014.4019 · 0.73 Impact Factor
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    ABSTRACT: IUCr Journals CRYSTALLOGRAPHY JOURNALS ONLINE This open-access article is distributed under the terms of the Creative Commons Attribution Licence http://creativecommons.org/licenses/by/2.0/uk/legalcode, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. Acta Cryst. (2014). E70, 148–152 Prior et al. · [CrCl 2 (C 12 H 26 N 4)]PF 6 and [CrCl 2 (C 14 H 30 N 4)]PF 6
    Acta Crystallographica Section E Structure Reports Online 08/2014; E(70):148-152. DOI:10.1107/S1600536814019072 · 0.35 Impact Factor
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    ABSTRACT: Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn(2+) complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn(2+). Few of the Cu(2+) and Fe(2+) complexes also showed improvement in activity but Ni(2+), Co(2+) and Zn(2+) complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development.
    Bioorganic & Medicinal Chemistry 05/2014; DOI:10.1016/j.bmc.2014.05.003 · 2.95 Impact Factor
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    ABSTRACT: Four copper(II) complexes and one copper(I) complex with pyridine-containing pyridylalkylamide ligands N-(pyridin-2-ylmethyl)pyrazine-2-carboxamide (HLpz) and N-(2-(pyridin-2-yl)ethyl)pyrazine-2-carboxamide (HLpz) were synthesized and characterized. The X-ray crystal structures of [Cu2(Lpz)2(4,4-bipy)(OTf)2] (1, OTf = trifluoromethanesulfonate, 4,4-bipy = 4,4-bipyridine) and [Cu(Lpz)(py)2]OTf·H2O (2, py = pyridine) revealed binuclear and mononuclear molecular species, respectively, while [Cu(Lpz)(μ 2-1,1-N3)]n (3), [Cu(Lpz)(μ 2-1,3-N3)]n (4), and [Cu(HLpz)Cl]n (5) are coordination polymer 1-D chains in the solid state.
    Journal of Coordination Chemistry 12/2013; 66(23). DOI:10.1080/00958972.2013.860451 · 2.22 Impact Factor
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    ABSTRACT: Tetraazamacrocyclic complexes of transition metals provide useful units for incorporating multiple coordination interactions into a single protein binding molecule. They can be designed with available sites for protein interactions via donor atom-containing amino acid side chains or labile ligands, such as H(2)O, allowing facile exchange. Three configurationally restricted nickel(ii) cyclam complexes with either one or two macrocyclic rings were synthesised and their ability to abrogate the CXCR4 chemokine receptor signalling process was assessed (IC(50) = 8320, 194 and 14 nM). Analogues were characterised crystallographically to determine the geometric parameters of the acetate binding as a model for aspartate. The most active nickel(ii) compound was tested in several anti-HIV assays against representative viral strains showing highly potent EC(50) values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC(50) > 125 μM).
    Dalton Transactions 08/2012; 41(37):11369-77. DOI:10.1039/c2dt31137b · 4.10 Impact Factor
  • J. Cody Timmons, Timothy J. Hubin
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    ABSTRACT: Covalently linked azamacrocycles have been known for several decades, but only a modest number of these ligands and their complexes had been described prior to 2000. Since that time, a number of new synthetic methods for their preparation have been discovered, yielding a growing collection of these interesting ligands. Additionally, the number of uses to which these ligands and their metal complexes have been applied has expanded. In this review, the important synthetic methods yielding linked azamacrocycles will be outlined, and their applications will be discussed.
    Coordination Chemistry Reviews 08/2010; 254(15-16-254):1661-1685. DOI:10.1016/j.ccr.2009.09.018 · 12.10 Impact Factor
  • ChemInform 07/2010; 30(28):no-no. DOI:10.1002/chin.199928301
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 02/2010; 31(7). DOI:10.1002/chin.200007035
  • Antiviral Research 05/2009; 82(2):A45. DOI:10.1016/j.antiviral.2009.02.100 · 3.43 Impact Factor
  • Antiviral Research 05/2009; 82(2). DOI:10.1016/j.antiviral.2009.02.141 · 3.43 Impact Factor
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    ABSTRACT: Dichloro(4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane)chromium(III) chloride, Dichloro(4,10-dibenzyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane) chromium(III) chloride, and Dichloro(4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2] hexadecane)chromium)(III) chloride have been prepared by the reaction of anhydrous chromium(III) chloride with the appropriate cross-bridged tetraazamacrocycle. Aquation of these complexes proved difficult, but Chlorohydroxo(4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane)chromium)(III) chloride was synthesized directly from chromium(II) chloride complexation followed by exposure or the reaction to air in the presence of water. The four complexes were characterized by X-ray crystal structure determination. All contain the chromium(III) ion in a distorted octahedral geometry and the macrocycle in the cis-V configuration, as dictated by the ethylene cross-bridge. Further characterization of the hydroxo complex reveals a magnetic moment of mu(eff) = 3.95 B.M. and electronic absorbtions in acetonitrile at lambda(max) = 583nm (epsilon = 65.8 L/cm.mol), 431nm (epsilon = 34.8 L/cm.mol) and 369nm (epsilon = 17 L/cm.mol).
    Inorganica Chimica Acta 04/2009; 362(6):2084-2088. DOI:10.1016/j.ica.2008.09.034 · 2.04 Impact Factor
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    ABSTRACT: A new copper(II) containing bis-macrocyclic CXCR4 chemokine receptor antagonist is shown to have improved binding properties to the receptor protein in comparison to the drug AMD3100 (Plerixafor, Mozobil). The interaction of the metallodrug has been optimized by using ultrarigid chelator units that offer an equatorial site for coordination to the amino acid side chains of the protein. Binding competition assays with anti-CXCR4 antibodies show that the new compound stays bound longer and it has improved anti-HIV potency in vitro (EC(50) = 4.3 nM). X-ray structural studies using acetate as a model for carboxylate amino acid side chains indicate the nature of the coordination interaction.
    Journal of the American Chemical Society 03/2009; 131(10):3416-7. DOI:10.1021/ja807921k · 11.44 Impact Factor
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    ABSTRACT: The pyrazine-containing ligands 1 (pyrazine-2-carboxylic acid (pyridine-2-ylmethyl)-amide) and 2 (pyrazine-2,5-dicarboxylic acid bis-[(pyridine-2-ylmethyl)-amide]) have been synthesized and characterized in order to probe their ability to form polynuclear transition metal complexes. A mixed oxidation state Co3+–Co2+–Co3+ complex with deprotonated ligand 1, [Co(1−)2Co(H2O)2Cl2Co(1−)2]Cl2, has been obtained and characterized by X-ray crystal structure determination. The central octahedral cobalt(II) ion in the complex is coordinated by one pyrazine nitrogen from each of the surrounding octahedral cobalt(III), ions which are meridianally coordinated by two of the ligands 1−. Key aspects of both ligands are their rigid meridianal coordination, coupled with the pyrazine core, which demands coordination of metal ions on opposite sides of the ligand strand.
    Inorganic Chemistry Communications 01/2008; 11(1):1-4. DOI:10.1016/j.inoche.2007.10.006 · 2.06 Impact Factor
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    ABSTRACT: The title compound, [FeCl2(C12H26N4)]PF6, is the first mononuclear Fe3+ complex of an ethylene cross-bridged tetraaza-macrocycle to be structurally characterized. Comparison with the mononuclear Fe2+ complex of the same ligand shows that the smaller Fe3+ ion is more fully encapsulated by the cavity of the bicyclic ligand. Comparison with the mu-oxo dinuclear complex of an unsubstituted ligand of the same size demonstrates that the methyl groups of 4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane prevent dimerization upon oxidation of the metal centre. Nax -Fe3+ -Nax bond angles (ax is axial), and thus the degree of encapsulation by the ligand, are quite different between the mononuclear and dinuclear mu-oxo species, which is probably the consequence of steric considerations.
    Acta Crystallographica Section C Crystal Structure Communications 12/2006; 62(Pt 11):m553-5. DOI:10.1107/S0108270106040765 · 0.54 Impact Factor
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    ABSTRACT: A zinc(II) containing configurationally restricted analogue of bismacrocyclic cyclam-type CXCR4 chemokine receptor antagonists has been synthesized and shown to adopt only one configuration in solution. The single crystal X-ray structure reveals favorable binding to acetate via a bidentate chelation that can be related to the proposed interaction with aspartate on the receptor protein surface. The zinc(II) complex is highly active against HIV infection in vitro.
    Journal of Medicinal Chemistry 11/2006; 49(21):6162-5. DOI:10.1021/jm0607810 · 5.48 Impact Factor
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    ABSTRACT: CCXCR4 belongs to the superfamily of seven transmembrane G-protein- coupled receptors that transduce signals via heterotrimeric G-proteins. CXCR4 and its ligand CXCL12 are widely expressed in normal tissues and play a fundamental role in many processes including fetal development and trafficking of naı¨ve lymphocytes. CXCR4 receptor has been determined to act as a co-receptor for HIV-1 and HIV-2 (X4) strains, and thus is a potential therapeutic target. Bis-azamacrocycles (BAZ) such as AMD3100 have been identified as potent inhibitors of HIV replication and CXCL12 by interacting with Asp171 and Asp262 of CXCR4. Incorporation of transition metals to AMD3100 increases the antiviral potency up to 36-fold. A series of configurationally restricted BAZ with an ethylene moiety were prepared which show improved binding properties to AMD3100. Configurationally restricted BAZ were evaluated for binding potency to CXCR4 by their ability to block the binding of CXCR4 specific mAbs. Configurationally restricted BAZ inhibited all mAbs more effectively than metal complexes of AMD3100. These configurationally restricted BAZ are attractive drug candidates for therapeutic intervention in which CXCR4 is critically involved.
    Immunology 01/2005; 116:75. · 3.74 Impact Factor
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    ABSTRACT: An unusual copper(ii) complex of a highly rigid and bulky ligand (a macrocycle-glyoxal condensate) has been synthesized and investigated via DFT calculations and structural characterisation.
    Chemical Communications 09/2004; DOI:10.1039/b405358c · 6.72 Impact Factor

Publication Stats

690 Citations
139.65 Total Impact Points


  • 2006–2014
    • Southwestern Oklahoma State University
      • • College of Pharmacy
      • • Department of Chemistry and Physics
      Weatherford, Oklahoma, United States
  • 1998–2010
    • Lawrence University
      • Chemistry
      Lawrence, Kansas, United States
  • 2004–2006
    • University of Hull
      • Department of Chemistry
      Hull, ENG, United Kingdom
  • 2003–2004
    • McPherson College
      • Natural Sciences
      Kansas, United States
  • 2000–2003
    • University of Kansas
      • Department of Chemistry
      Lawrence, KS, United States
  • 1999–2003
    • The University of Warwick
      • Department of Chemistry
      Warwick, ENG, United Kingdom