Maurer Richard I, Blower Philip J, Dilworth Jonathan R, Reynolds Christopher A, Zheng Yifan, Mullen Gregory E D
Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom.
J Med Chem. 2002 Mar 28;45(7):1420-31. doi: 10.1021/jm0104217.
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.
双乙酰双（N4-甲基硫代氨基脲）铜（Cu(II)ATSM）是一种很有前景的用于缺氧组织成像的试剂。在此，我们展示的结果有助于深入了解先前观察到的构效关系背后的化学和电子性质。基于Cu(II)PTSM的已知结构，对一系列13种具有不同烷基化模式且几何结构固定的Cu(II)双（硫代氨基脲）类似物的电子结构和分子轨道进行密度泛函理论（DFT）计算，结果表明最低未占分子轨道（LUMO）和次低轨道的能量非常接近，并且它们的能量顺序显著依赖于配体烷基化模式，其方式与缺氧选择性和氧化还原电位相关。Cu(II)ATSM和其他缺氧选择性类似物的LUMO主要基于金属（导致单重态还原物种），而Cu(II)PTSM和其他非选择性类似物的LUMO主要基于配体（导致三重态还原物种）。在Cu(II)ATSM和Cu(II)GTS中放松几何约束并进行完全优化后，基于金属的轨道成为LUMO，并且单重态是还原物种的热力学优选形式。化学和电化学研究表明，所有Cu(II)配合物都可还原，但Cu(I)PTSM和其他非选择性类似物在还原时会立即解离并释放配体（通过紫外可见光谱检测），而Cu(I)ATSM和其他缺氧选择性类似物则不会。相反，它们会被分子氧迅速重新氧化为Cu(II)配合物。非选择性配合物Cu(II)PTSM和Cu(II)GTS的可逆电化学还原在弱酸存在下变得不可逆，而Cu(II)ATSM的则不受影响。鉴于这些结果，我们提出了一个基于电子结构和分子振动来解释构效关系的模型。
