McRobbie Graeme, Valks Gina C, Empson Christopher J, Khan Abid, Silversides Jon D, Pannecouque Christophe, De Clercq Erik, Fiddy Steven G, Bridgeman Adam J, Young Nigel A, Archibald Stephen J
Department of Chemistry, The University of Hull, Cottingham Road, Hull, UK HU6 7RX.
Dalton Trans. 2007 Nov 21(43):5008-18. doi: 10.1039/b705800d. Epub 2007 Oct 2.
The syntheses of configurationally restricted mono- and bis-macrocyclic copper(II) perchlorate complexes (copper(II) 5-benzyl-1,5,8,12-tetraazabicyclo[10.2.2]hexadecane and dicopper(II) 5,5'-[1,4-phenylenebis(methylene)]-bis(1,5,8,12-tetraazabicyclo[10.2.2]hexadecane)) are reported and the X-ray structure of the copper(II) mono-macrocyclic complex has been determined. EXAFS studies on the bis-macrocyclic species in aqueous solution show that the copper coordination spheres are essentially identical to the solid state structure, and do not vary in the presence of 20 equivalents of sodium acetate per metal centre. DFT calculations were carried out at the BP86/TZP level to determine the nature of potential binding interactions with CXCR4 aspartate residues. The alkylated single macrocyclic compound was modelled with an acetate included to represent the aspartate residue, demonstrating that the predicted macrocycle configuration has the lowest energy and the acetate interaction is effectively monodentate giving a distorted trigonal bipyramidal geometry at the copper centre. In vitro anti-HIV infection assays show that the configurationally restricted dicopper(II) complex is more active (average EC(50) = 0.026 microM against HIV-1) than the non-constrained dicopper(II) 1,1'-[1,4-phenylenebis(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane) (average EC(50) = 0.047 microM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(II) complex.
报道了构型受限的单环和双环高氯酸铜（II）配合物（铜（II）5-苄基-1,5,8,12-四氮杂双环[10.2.2]十六烷和二铜（II）5,5'-[1,4-亚苯基双（亚甲基）]-双（1,5,8,12-四氮杂双环[10.2.2]十六烷））的合成，并测定了铜（II）单环配合物的X射线结构。对水溶液中的双环物种进行的扩展X射线吸收精细结构（EXAFS）研究表明，铜的配位球与固态结构基本相同，并且在每个金属中心存在20当量乙酸钠的情况下不会发生变化。在BP86/TZP水平上进行了密度泛函理论（DFT）计算，以确定与CXCR4天冬氨酸残基潜在结合相互作用的性质。用包含乙酸盐的模型模拟烷基化的单环化合物以代表天冬氨酸残基，表明预测的大环构型具有最低能量，并且乙酸盐相互作用有效地为单齿，在铜中心给出扭曲的三角双锥几何形状。体外抗HIV感染试验表明，构型受限的二铜（II）配合物比无限制的二铜（II）1,1'-[1,4-亚苯基双（亚甲基）]-双（1,4,8,11-四氮杂环十四烷）更具活性（对HIV-1的平均半数有效浓度（EC50）= 0.026 microM）（对HIV-1的平均EC50 = 0.047 microM），尽管其活性比构型受限的二锌（II）配合物低一个数量级。
