Frank W Kotch

University of Maryland, College Park, Maryland, United States

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Publications (9)60.45 Total impact

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    ABSTRACT: Using solid-state (23)Na NMR and quantum chemical calculations we have found that the Na(+) ion bound to a calix[4]arene-guanosine conjugate dimer resides slightly above the G-quartet plane and simultaneously coordinates to a water molecule in a square-pyramidal (penta-coordination) geometry.
    Chemical Communications 05/2009; · 6.38 Impact Factor
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    ABSTRACT: This paper illustrates the use of a kinetically controlled exchange reaction to effect regioselective modification of a hydrogen-bonded assembly. Both the bound anion and cation can control the exchange of ligand into the different layers of a synthetic G-quadruplex.
    Organic Letters 12/2004; 6(23):4265-8. · 6.14 Impact Factor
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    ABSTRACT: In this paper, we report on the formation and properties of a water-stabilized dimer comprising calix[4]arene-guanosine conjugate cG 2. The 1,3-alternate calixarene cG 2 was poorly soluble in dry CDCl(3) and gave an ill-resolved NMR spectrum, consistent with its nonspecific aggregation. The compound was much more soluble in water-saturated CDCl(3). Two sets of well-resolved (1)H NMR signals for the guanosine residues in cG 2, present in a 1:1 ratio, indicated that the compound's D(2) symmetry had been broken and provided the first hint that cG 2 dimerizes in water-saturated CDCl(3). The resulting dimer, (cG 2)(2).(H(2)O)(n)(), has a unique property: it extracts alkali halide salts from water into organic solution. This dimer is a rare example of a self-assembled ion pair receptor. The identity of the (cG 2)(2).NaCl.(H(2)O)(n)() dimer was confirmed by comparing its self-diffusion coefficient in CDCl(3), determined by pulsed-field gradient NMR, with that of control compound cA 3, an adenosine analogue. The dimer's stoichiometry was also confirmed by quantitative measurement of the cation and anion using ion chromatrography. Two-dimensional NMR and ion-induced NMR shifts indicated that the cation binding site is formed by an intermolecular G-quartet and the anion binding site is provided by the 5'-amide NH groups. Once bound, the salt increases the dimer's thermal stability. Both (1)H NMR and ion chromatography measurements indicated that the cG 2 dimer has a modest selectivity for extracting K(+) over Na(+) and Br(-) over Cl(-). The anion's identity also influences the association process: NaCl gives a soluble, discrete dimer whereas addition of NaBPh(4) to (cG 2)(2).(H(2)O)(n)() leads to extensive aggregation and precipitation. This study suggests a new direction for ion pair receptors, namely, the use of molecular self-assembly. The study also highlights water's ability to stabilize a functional noncovalent assembly.
    Journal of the American Chemical Society 01/2004; 125(49):15140-50. · 10.68 Impact Factor
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    ABSTRACT: This contribution describes the discovery and properties of a synthetic, low-molecular weight compound that transports Cl- across bilayer membranes. Such compounds have potential as therapeutics for cystic fibrosis and cancer. The H+/Cl- co-transport activities of acyclic tetrabutylamides 1-6 were compared by using a pH-stat assay with synthetic EYPC liposomes. The ion transport activity of the most active compound, trimer 3, was an order of magnitude greater than that of calix[4]arene tetrabutylamide C1 a macrocycle known to function as a synthetic ion channel. Trimer 3 has an unprecedented function for a synthetic compound, as it induces a stable potential in liposomes experiencing a transmembrane Cl-/SO42- gradient. Data from both pH-stat and 35Cl NMR experiments indicate that 3 co-transports H+/Cl-. Although 3 transports both Cl- and H+ the overall process is not electrically silent. Thus, trimer 3 induces a stable potential in LUVs due to a transmembrane anionic gradient. The ability of trimer 3 to transport Cl-, to maintain a transmembrane potential, along with its high activity at uM concentrations, its low molecular weight, and its simple preparation, make this compound a valuable lead in drug development for diseases caused by Cl- transport malfunction.
    Journal of the American Chemical Society 04/2003; 125(10):2840-1. · 10.68 Impact Factor
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    ABSTRACT: Nucleic acid quadruplexes are composed of guanine quartets stabilized by specific metal ions. X-ray diffraction can provide high-resolution information on the structure and metal binding properties of quadruplexes, but only if they can be crystallized. NMR can provide detailed information on the solution structure of such quadruplexes but little quantitative data concerning the metal binding site. Here we apply extended X-ray absorption fine structure (EXAFS) measurements to characterize the metal ion binding site, in frozen solution, of the unimolecular quadruplex formed by the thrombin binding aptamer, d(G(2)T(2)G(2)TGTG(2)T(2)G(2)) (TBA), in the presence of Pb(2+) ions. The Pb L(III) -edge X-ray absorption spectrum of this metal-DNA complex is very similar to that we obtain for a Pb(2+)-stabilized quartet system of known structure constructed from a modified guanine nucleoside (G1). The Fourier transforms of the Pb(2+) complexes with both TBA and G1 show a first-shell interaction at about 2.6 A, and a weaker, broader shell at 3.5-4.0 A. Quantitative analysis of the EXAFS data reveals the following: (i) very close agreement between interatomic distances at the metal coordination site for the Pb(2+)-G1 complex determined by EXAFS and by X-ray crystallography; (ii) similarly close agreement between interatomic distances measured by EXAFS for the Pb(2+)-G1 and Pb(2+)-TBA complexes. These results provide strong evidence for binding of the Pb(2+) ion in the region between the two quartets in the Pb(2+)-TBA complex, coordinated to the eight surrounding guanine O6 atoms. The specific binding of Pb(2+) to DNA examined here may be relevant to the genotoxic effects of this environmentally important heavy metal. Furthermore, these results demonstrate the utility of EXAFS as a method for quantitative characterization of specific metal binding sites in nucleic acids in solution.
    Biochemistry 11/2002; 41(40):12133-9. · 3.38 Impact Factor
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    ABSTRACT: The ion transport activity of calix[4]arene tetrabutylamide 1,3-alt 2 was studied in liposomes, planar lipid bilayers, and HEK-293 cells. These experiments, when considered together with (1)H NMR and X-ray crystallography data, indicate that calix[4]arene tetrabutylamide 2 (1) forms ion channels in bilayer membranes, (2) mediates ion transport across cell membranes at positive holding potential, (3) alters the pH inside liposomes experiencing a Cl(-) gradient, and (4) shows a significant Cl(-)/SO(4)(2)(-) transport selectivity. An analogue, calix[4]arene tetramethylamide 1, self-assembles in the presence of HCl to generate solid-state structures with chloride-filled and water-filled channels. Structureminus signactivity studies indicate that the hydrophobicity, amide substitution, and macrocyclic framework of the calixarene are essential for HCl binding and transport. Calix[4]arene tetrabutylamide 2 is a rare example of an anion-dependent, synthetic ion channel.
    Journal of the American Chemical Society 04/2002; 124(10):2267-78. · 10.68 Impact Factor
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    FW Kotch, JC Fettinger, JT Davis
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    ABSTRACT: The lipophilic nucleoside, G 1, extracts Pb(2+) picrate from water into organic solvents to give structures based on the hydrogen-bonded G-quartet. Crystal structures indicate important differences between (G 1)(8)-Pb(2+) and (G 1)(8)-K(+). The divalent Pb(2+) templates a smaller G(8) cage than does K(+), as judged by the M-O6 bond length, O6-O6 diagonal distance, and inter-tetramer separation. The more compact Pb(2+) octamer correlates with NMR data indicating that N2-N7 hydrogen bonds in (G 1)(8)-Pb(2+) are kinetically more stable than in (G 1)(8)-K(+).
    Organic Letters 11/2000; 2(21):3277-80. · 6.14 Impact Factor
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    ABSTRACT: In the presence of Na+, a 1,3-alternate-calix[4]arene bearing four guanosine units forms a self-assembled nanotube.
    Chemical Communications 01/2000; · 6.38 Impact Factor
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    ABSTRACT: A compound containing at least two aromatic rings covalently bonded together, with each aromatic ring containing at least one oxyacetamide-based side chain, the compound being capable of forming a chloride ion channel across a lipid bilayer, and transporting chloride ion across the lipid bilayer.