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

Abstract

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.

• Authors: Richard I Maurer, Philip J Blower, Jonathan R Dilworth, Christopher A Reynolds, Yifan Zheng, Gregory E D Mullen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 7 Pg. 1420-31 (Mar 28 2002) ISSN: 0022-2623 [Print] United States
• PMID: 11906283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Coordination Complexes
• Free Radical Scavengers
• Ligands
• Organometallic Compounds
• Radiopharmaceuticals
• Thiosemicarbazones
• copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)
• Copper

Topics

• Algorithms
• Coordination Complexes
• Copper (chemistry)
• Electrons
• Free Radical Scavengers
• Hydrogen-Ion Concentration
• Hypoxia
• Ligands
• Models, Chemical
• Models, Molecular
• Models, Theoretical
• Organometallic Compounds (chemistry, pharmacology)
• Oxidation-Reduction
• Radiopharmaceuticals (pharmacology)
• Software
• Spectrophotometry
• Structure-Activity Relationship
• Thiosemicarbazones (chemistry, pharmacology)
• Ultraviolet Rays