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 π-orbital immediately above the LUMO,
while the LUMO itself has dx2-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 π-orbital rather than dx2-y2. Density functional calculations on the putative singlet Cu(I)-reduced species suggest that this ligand π-character could be brought about by distortion away from planarity
during reduction, allowing the low-lying ligand π-LUMO to mix into the dx2-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.

本研究首次合成了双(硒代半卡巴腙)合铜（copper bis(selenosemicarbazone)）配合物，所使用的配体包括乙二醛双(硒代半卡巴腙)、丙酮醛双(硒代半卡巴腙)与2,3-丁二酮双(硒代半卡巴腙)。光谱性质表征结果表明，该类配合物与经典的平面正方形含硫对应物——双(硫代半卡巴腙)合铜配合物结构相似。通过对含硫与含硒配合物的光谱对比分析，可深入揭示其电子结构特征。针对以硒取代硫、以及在配体骨架上逐步引入甲基对配合物光谱与氧化还原性质的影响，本研究结合自旋非限制性密度泛函计算（spin-unrestricted density functional calculations）从电子结构层面进行了合理化阐释。计算结果显示，与含硫对应物类似，该类配合物在最低未占据分子轨道（Lowest Unoccupied Molecular Orbital, LUMO）上方存在一个能级极低的配体基π轨道，而LUMO本身具有dx²-y²轨道特征（即与最高占据分子轨道（Highest Occupied Molecular Orbital, HOMO）为自旋配对轨道）。将配体中的硫原子替换为硒原子对氧化电位的影响远大于还原电位，而对配体骨架进行烷基化修饰则对还原电位的影响更为显著。这一结果提示，氧化与还原过程涉及空间分布不同的轨道：还原物种中额外的电子占据配体基π轨道，而非dx²-y²轨道。对假定的单重态Cu(I)还原物种进行密度泛函计算后发现，还原过程中配合物偏离平面结构的畸变可使低能配体π-LUMO与基于dx²-y²的HOMO发生轨道混合，从而赋予该还原物种配体π轨道特征。鉴于含硫与含硒配合物在结构与还原行为上的相似性，采用铜的正电子发射同位素（Cu-60、Cu-62、Cu-64）标记该类配合物有望作为放射性药物，用于组织灌注与缺氧成像的生物学评价。