Biomedical subjects

Richard I Maurer

Publications and source records attributed to Richard I Maurer.

4 recordsLinked to original sources

PubMed2005

Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase.

A library of polyamine-peptide conjugates based around some previously identified inhibitors of trypanothione reductase was synthesised by parallel solid-phase chemistry and screened. Kinetic analysis of library members established that subtle structural changes altered their mechanism of action, switching between competitive and non-competitive inhibition. The mode of action of the non-competitive inhibitors was investigated in detail by a variety of techniques including enzyme kinetic analysis (looking at both NADPH and trypanothione disulfide substrates), gel filtration chromatography and analytical ultracentrifugation, leading to the identification of an allosteric mode of inhibition.

Chromatography, Gel↗

PubMed2004

A multilayered approach to approximating solute polarization.

A hybrid multilayered "ONIOM"-type approach to solvation is presented in which the basic free energy of hydration is taken from the Poisson Boltzmann method and the contribution to the solute polarization is taken from a quantum mechanical implementation of the Born method. The method has been tested on the 52 neutral molecules used in the AM1-SM2 parameterization, and the polarized continuum method is taken as the standard by which the results are assessed. Regression analysis shows that the method gives a small improvement over the standard Poisson Boltzmann method or a dramatic improvement over the Born method. The system presented here represents one of the more straightforward applications of the multilayered approach to solvation, but other more sophisticated approaches are discussed.

Journal Article↗

PubMed2003

Hypoxia-targeting copper bis(selenosemicarbazone) complexes: comparison with their sulfur analogues.

The first copper bis(selenosemicarbazone) complexes have been synthesized, using the ligands glyoxal bis(selenosemicarbazone), pyruvaldehyde bis(selenosemicarbazone), and 2,3-butanedione bis(selenosemicarbazone). Their spectroscopic properties indicate that they are structurally analogous to their well-known square-planar sulfur-containing counterparts, the copper bis(thiosemicarbazone) complexes. Spectroscopic comparison of the sulfur- and selenium-containing complexes provides insight into their electronic structure. The effects on spectroscopic and redox properties of replacing sulfur with selenium, and of successive addition of methyl groups to the ligand backbone, are rationalized in terms of their electronic structure using spin-unrestricted density functional calculations. These suggest that, like the sulfur analogues, the complexes have a very low-lying empty ligand-based pi-orbital immediately above the LUMO, while the LUMO itself has d(x2)-(y2) character (i.e., is the spin partner of the HOMO). Replacement of S by Se shifts the oxidation potentials much more than the reduction potentials, whereas alkylation of the ligand backbone shifts the reduction potentials more than the oxidation potentials. This suggests that oxidation and reduction involve spatially different orbitals, with the additional electron in the reduced species occupying the ligand-based pi-orbital rather than d(x2)-(y2). Density functional calculations on the putative singlet Cu(I)-reduced species suggest that this ligand pi-character could be brought about by distortion away from planarity during reduction, allowing the low-lying ligand pi-LUMO to mix into the d(x2)-(y2)-based HOMO. The analogy in the structure and reduction behavior between the sulfur- and selenium-containing complexes suggests that labeled with positron emitting isotopes of copper (Cu-60, Cu-62, Cu-64), the complexes warrant biological evaluation as radiopharmaceuticals for imaging of tissue perfusion and hypoxia.

Copper↗

PubMed2002

Studies on the mechanism of hypoxic selectivity in copper bis(thiosemicarbazone) radiopharmaceuticals.

Copper diacetyl-bis(N4-methylthiosemicarbazone), Cu(II)ATSM, is a promising agent for imaging hypoxic tissue. Here we present results that provide insight into the chemical and electronic properties underlying previously observed structure-activity relationships. Density functional theory (DFT) calculations on the electronic structures and molecular orbitals of a series of 13 Cu(II)bis(thiosemicarbazone) analogues with different alkylation patterns and with fixed geometries based on the known structure of Cu(II)PTSM showed that the LUMO and the next lowest orbital were very close in energy, and their energy order was strikingly dependent on the ligand alkylation pattern in a way that correlated with hypoxia-selectivity and redox potentials. The LUMOs of Cu(II)ATSM and other hypoxia-selective analogues were predominantly metal-based (leading to a singlet reduced species) while the LUMOs of Cu(II)PTSM and other nonselective analogues were predominantly ligand-based (leading to a triplet reduced species). Upon relaxation of the geometric constraint and full optimization in both Cu(II)ATSM and Cu(II)GTS, the metal-based orbital became the LUMO, and the singlet was the thermodynamically preferred form of the reduced species. Chemical and electrochemical investigation showed that all Cu(II) complexes were reducible, but Cu(I)PTSM and other nonselective analogues dissociated immediately upon reduction with release of ligand (detected by UV-vis) while Cu(I)ATSM and other hypoxia-selective analogues did not. Instead they were rapidly re-oxidized to the Cu(II) complex by molecular oxygen. The reversible electrochemical reduction of nonselective complexes Cu(II)PTSM and Cu(II)GTS became irreversible in the presence of weak acid, whereas that of Cu(II)ATSM was unaffected. In light of these results we present a model to explain the structure-activity relationships on the basis of electronic structure and molecular vibrations.

Algorithms↗