Publications by authors named "Daniel C. Hill"

5 Publications

  • Page 1 of 1

Isomeric trimethylene and ethylene pendant-armed cross-bridged tetraazamacrocycles and in vitro/in vivo comparisions of their copper(II) complexes.

Inorg Chem 2011 Apr 7;50(7):3078-86. Epub 2011 Mar 7.

Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, USA.

Ethylene cross-bridged tetraamine macrocycles are useful chelators in coordination, catalytic, medicinal, and radiopharmaceutical chemistry. Springborg and co-workers developed trimethylene cross-bridged analogues, although their pendant-armed derivatives received little attention. We report here the synthesis of a bis-carboxymethyl pendant-armed cyclen with a trimethylene cross-bridge (C3B-DO2A) and its isomeric ethylene-cross-bridged homocyclen ligand (CB-TR2A) as well as their copper(II) complexes. The in vitro and in vivo properties of these complexes are compared with respect to their potential application as (64)Cu-radiopharmaceuticals in positron emission tomography (PET imaging). The inertness of Cu-C3B-DO2A to decomplexation is remarkable, exceeding that of Cu-CB-TE2A. Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible. The reaction conditions for preparing (64)Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to (64)Cu-CB-TR2A (basic ethanol). The in vivo behavior of the (64)Cu complexes was evaluated in normal rats. Rapid and continual clearance of (64)Cu-CB-TR2A through the blood, liver, and kidneys suggests relatively good in vivo stability, albeit inferior to (64)Cu-CB-TE2A. Although (64)Cu-C3B-DO2A clears continually, the initial uptake is high and only about half is excreted within 22 h, suggesting poor stability and transchelation of (64)Cu to proteins in the blood and/or liver. These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.
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http://dx.doi.org/10.1021/ic200014wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065210PMC
April 2011

De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist.

J Med Chem 2010 Feb;53(4):1876-80

Department of CNS Chemistry, AstraZeneca Pharmaceuticals,1800 Concord Pike, Wilmington, Delaware 19850, USA.

We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor.
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http://dx.doi.org/10.1021/jm901200tDOI Listing
February 2010

General methods for flash chromatography using disposable columns.

Mol Divers 2009 May 13;13(2):247-52. Epub 2009 Jan 13.

Exelixis, Inc., San Diego, CA, USA.

As technology has evolved available guidelines for normal-phase flash chromatography have become less relevant. Years of experience performing chromatography with disposable columns have been condensed into simple guidelines useful for translating TLC results into either isocratic- or gradient-flash chromatography. The described studies should provide researchers with a means of selecting adequate columns and guidelines to reduce the waste of solvents, silica, time, and money.
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http://dx.doi.org/10.1007/s11030-008-9104-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780649PMC
May 2009

Inside or outside a ligand cleft? Synthetic, structural, and kinetic inertness studies of zinc, cadmium, and mercury complexes of cross-bridged cyclam and cyclen.

Dalton Trans 2004 Nov 28(21):3536-47. Epub 2004 Sep 28.

Department of Chemistry, University of New Hampshire, Durham 03824, USA.

Ethylene cross-bridging of the popular tetraazamacrocyclic ligand cyclam has led to metal complexes with enhanced kinetic inertness. The synthesis and spectral characterization of zinc(II), cadmium(II), and mercury(II) complexes of cross-bridged cyclam (L1) as well as cross-bridged cyclen (L2) are reported along with the details of our synthetic route to L2. X-ray structural studies revealed that all Zn(II) and Cd(II) cations are fully kappa(4)N-coordinated inside the respective ligand's molecular cleft with L1 providing the better fit for Zn(II). While Hg(II) is similarly coordinated to L2, it has been found to complex L1 outside the ligand cleft in a novel exo-kappa(2)N-mode. Solution NMR data of the kappa(4)N complexes are consistent with the presence of only a single cis-folded isomer in each case. Ligand (1)H and (13)C coupling to both (111,113)Cd and (199)Hg in their complexes can be clearly discerned. The relative kinetic inertness of representative cross-bridged complexes in acidic aqueous solution has been assessed and found to be in the following order: Zn(II) > Cd(II)[dbl greater-than] Hg(II). The data also reaffirm that cross-bridged cyclam ligand L1 forms a substantially more inert complex with zinc(II) than either the smaller cyclen analogue L2 or the unbridged 1,4,8,11-tetramethyl-cyclam L3.
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http://dx.doi.org/10.1039/b410738aDOI Listing
November 2004

Synthesis of Lipophilic Paramagnetic Contrast Agents.

J Org Chem 1999 Apr;64(8):2683-2689

Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801.

The facile, high-yielding synthesis of a series of macrocycles 7a-k in 75-100% yield is reported. The transformation of these compounds to their carboxymethylated analogues 8a-k in 75-90% yield and subsequent gadolinium complexes 9a-k provides a series of homologous neutral paramagnetic contrast agents (PCAs) with tunable lipophilicity. Alkylated cationic intermediates 6a-k are prepared in yields of 72-94% from glyoxal adduct of cyclen (5) and slight excesses of alkyl iodides. The methodology is selective for monoalkylation and amenable to large-scale synthesis.
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http://dx.doi.org/10.1021/jo981920rDOI Listing
April 1999