Liang Xiangyang, Weishäupl Michael, Parkinson John A, Parsons Simon, McGregor Pamela A, Sadler Peter J
School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK.
Chemistry. 2003 Oct 6;9(19):4709-17. doi: 10.1002/chem.200304808.
The interaction of metal cyclams with carboxylate groups is thought to play an important role in their binding to the CXCR4 chemokine receptor and in their anti-HIV activity. Here we report the synthesis of acetate, phthalate, perchlorate and chloride complexes of Zn(II) cyclam (1,4,8,11-tetraazacyclotetradecane). The X-ray crystal structures of Zn(cyclam)(phthalate)(CH(3)OH)(2n) and Zn(cyclam)(H(2)O)(2)(2) contain octahedral Zn(II) centres. Phthalate acts as a bridging ligand in the former complex, binding through monodentate carboxylate groups, and giving rise to infinite chains in the lattice together with extensive hydrogen bonding between carboxylate donor oxygen atoms and amine and methanol acceptor atoms. The uncoordinated acetate groups and the aqua ligand in the acetate complex are also involved in a rich network of hydrogen bonds and this may account for the unusually long Zn[bond]O distance (2.27 A). In both crystalline complexes, the macrocycle adopts the trans-III (S,S,R,R) configuration. 1D (1)H NMR spectra of all four complexes have been fully assigned by a combination of 2D [(1)H, (1)H] COSY and TOCSY, and [(1)H, (13)C] and [(1 )H, (15)N] HSQC NMR data. In aqueous solution, the stable trans-III configuration found in the solid-state equilibrates slowly (hours at 298 K) with trans-I (R,S,R,S) and cis-V (R,R,R,R) configurations. The trans-III configuration is predominant in aqueous solution for both the chloride and perchlorate complexes, but for the acetate and phthalate complexes, the cis-V configuration dominates. Carboxylate groups appear to stabilize the cis-V configuration in solution through Zn(II) coordination and hydrogen bonding. Titration of the chloride Zn(II)-cyclam complex with acetate confirmed that carboxylates strongly induce formation of the cis-V configuration. This implies that carboxylates can exert a strong influence over configurational selectivity. Cyclam NH hydrogen bonding is prevalent both in the solid state and in solution, and is relevant to the anti-HIV activity of Zn(II) and other metal cyclam complexes and to their ability to recognize the CXCR4 transmembrane co-receptor.
金属环胺与羧酸根基团的相互作用被认为在它们与CXCR4趋化因子受体的结合及其抗HIV活性中起着重要作用。在此，我们报告了锌（II）环胺（1,4,8,11-四氮杂环十四烷）的乙酸盐、邻苯二甲酸盐、高氯酸盐和氯化物配合物的合成。Zn(环胺)(邻苯二甲酸盐)(CH₃OH)(2n)和Zn(环胺)(H₂O)₂₂的X射线晶体结构包含八面体锌（II）中心。在前者配合物中，邻苯二甲酸盐作为桥连配体，通过单齿羧酸根基团配位，并在晶格中形成无限链，同时羧酸根供体氧原子与胺和甲醇受体原子之间存在广泛的氢键。乙酸盐配合物中未配位的乙酸根基团和水配体也参与了丰富的氢键网络，这可能解释了异常长的Zn[键]O距离（2.27 Å）。在这两种晶体配合物中，大环均采用反式-III（S,S,R,R）构型。通过二维[(¹H,¹H) COSY和TOCSY以及[(¹H,¹³C]和[(¹H,¹⁵N] HSQC NMR数据的组合，已完全归属了所有四种配合物的一维(¹H) NMR光谱。在水溶液中，固态中发现的稳定反式-III构型与反式-I（R,S,R,S）和顺式-V（R,R,R,R）构型缓慢（298 K下数小时）平衡。对于氯化物和高氯酸盐配合物，反式-III构型在水溶液中占主导，但对于乙酸盐和邻苯二甲酸盐配合物，顺式-V构型占主导。羧酸根基团似乎通过锌（II）配位和氢键在溶液中稳定顺式-V构型。用乙酸盐滴定氯化锌（II）-环胺配合物证实，羧酸根强烈诱导顺式-V构型的形成。这意味着羧酸根可对构型选择性产生强烈影响。环胺NH氢键在固态和溶液中均普遍存在，并且与锌（II）和其他金属环胺配合物的抗HIV活性及其识别CXCR4跨膜共受体的能力相关。
