Liang Xiangyang, Parkinson John A, Weishäupl Michael, Gould Robert O, Paisey Stephen J, Park Hye-seo, Hunter Tina M, Blindauer Claudia A, Parsons Simon, Sadler Peter J
Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK.
J Am Chem Soc. 2002 Aug 7;124(31):9105-12. doi: 10.1021/ja0260723.
As platforms for the design of metal-based therapeutic and diagnostic agents, macrocycles are rigid enough to provide strong metal binding sites and orient functional groups stereoselectively, yet flexible enough to accommodate structural changes required for induced-fit recognition of biological targets. We consider the recognition of the Zn(II) complex of the bis-tetraazamacrocycle xylyl-bicyclam, a potent anti-HIV agent, by the coreceptor CXCR4, a G-protein-coupled receptor used by HIV for membrane fusion and cell entry. NMR studies show that the macrocycles of Zn(II)(2)-xylyl-bicyclam perchlorate exist in aqueous solution as two major configurations, trans-I (nitrogen chirality R,S,R,S), and trans-III (S,S,R,R). Acetate addition induced a major structural change. X-ray crystallography shows that the acetate complex contains the unusual cis-V cyclam configuration (R,R,R,R and folded) with bidentate coordination of acetate to Zn(II) plus second-coordination-sphere double H-bond formation between diagonal NH protons on the opposite cyclam face and acetate carboxylate oxygens. Detailed 1D and 2D NMR studies show that the major configuration of Zn(II)(2)-xylyl-bicyclam acetate in aqueous solution is cis-V/trans-I. Molecular modeling shows that an analogous cis-V site can be formed when Zn(II)(2)-xylyl-bicyclam binds to CXCR4, involving the carboxylate groups of Asp262 (Zn(II) coordination) and Glu288 (double H-bonding). The second cyclam can adopt the trans-I (or trans-III) configuration with Zn(II) binding to Asp171. These interactions are consistent with the known structure-activity relationships for bicyclam anti-HIV activity and receptor mutation. Consideration of the anti-HIV activity of xylyl-bicyclam complexes of other metal ions suggests that affinity for carboxylates, configurational flexibility, and kinetic factors may all play roles in receptor recognition. For example, Pd(II) cyclam complexes interact only weakly with axial ligands and are inflexible and inactive, whereas Co(III) cyclams bind carboxylates strongly, are configurationally flexible, and yet have low activity. Our findings should aid the design of new generations of active macrocycles including highly specific chemokine receptor antagonists.
作为金属基治疗和诊断剂设计的平台，大环化合物具有足够的刚性以提供强大的金属结合位点并立体选择性地定位官能团，同时又具有足够的灵活性以适应诱导契合识别生物靶标所需的结构变化。我们考虑了双四氮杂大环二甲苯基双环胺（一种有效的抗HIV药物）的锌（II）配合物与共受体CXCR4（HIV用于膜融合和细胞进入的G蛋白偶联受体）之间的识别。核磁共振研究表明，高氯酸锌（II）-二甲苯基双环胺的大环化合物在水溶液中以两种主要构型存在，反式-I（氮手性R,S,R,S）和反式-III（S,S,R,R）。添加醋酸盐会引起主要的结构变化。X射线晶体学表明，醋酸盐配合物包含不寻常的顺式-V环胺构型（R,R,R,R且折叠），醋酸盐与锌（II）形成双齿配位，并且在相对环胺面上的对角NH质子与醋酸盐羧基氧之间形成第二配位层双氢键。详细的一维和二维核磁共振研究表明，锌（II）-二甲苯基双环胺醋酸盐在水溶液中的主要构型是顺式-V/反式-I。分子模拟表明，当锌（II）-二甲苯基双环胺与CXCR4结合时，可以形成类似的顺式-V位点，涉及Asp262的羧基（锌（II）配位）和Glu288的羧基（双氢键）。第二个环胺可以采用反式-I（或反式-III）构型，锌（II）与Asp171结合。这些相互作用与双环胺抗HIV活性和受体突变的已知构效关系一致。对其他金属离子的二甲苯基双环胺配合物的抗HIV活性的考虑表明，对羧酸盐的亲和力、构型灵活性和动力学因素可能都在受体识别中起作用。例如，钯（II）环胺配合物与轴向配体的相互作用较弱，不灵活且无活性，而钴（III）环胺则与羧酸盐强烈结合，构型灵活，但活性较低。我们的发现应有助于设计新一代活性大环化合物，包括高度特异性的趋化因子受体拮抗剂。
