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.

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The coordination-directed self-assembly approach is an extremely powerful strategy for the synthesis of various 2-and 3D metallasupramolecules and can provide a structural and functional basis for its potential application toward molecular sensing and catalysis by using supramolecular chemistry.[1] In particular, discrete 3D self-assemblies derived from the multiple noncovalent interactions between monomeric metallo-subunits, such as chains, squares, and/or cages, are very intriguing because they are structurally complex but symmetrically simple and synthetically convenient to make. [2] Whereas various functional groups have been utilized for such purposes, little attention has been paid to metal-halide bonds, although they are well known as hydrogen-bond acceptors in molecular recognition and crystal engineering.[3] The halides are usually destined to be eliminated, presumably as a result of limited coordination sites on the metal center for incoming ligands.[1] These facts prompted us to explore the way to get the metal-halide groups to participate in both the coordination-directed and noncovalent self-assembly processes without their abstraction. Considering the molecular library model, [1g] we envisioned that the octahedral geometry of a transition metal might provide a novel approach for the use of metal-halide bonds as a self-assembly motif. For example, octahedral transition-metal centers with axial halide and cisprotecting ligands could serve as a 908 building block. The axial halide, then, may participate in hydrogen bonding with suitably functionalized bridging ligands.Herein, we demonstrate the unprecedented self-complementary dimer of Ru II metallamacrocycles which uses the intact metal-halide bonds in the coordination-directed selfassembly process and its reversible dissociation/association behavior, which is controlled by halide anions in solution.The ligand N,N'-bis(pyridin-4-yl)pyridine-2,6-dicarboxamide (1) was quite suitable for our purpose because it has central amide protons as hydrogen-bonding donors and is well known for bridging two metal centers, thus giving metallamacrocycles.[4] In addition, its bisamide configuration has proven to be very useful in hydrogen-bonding-mediated rotaxane formation [5] and anion recognition [6] with metallasupramolecules. As a precursor for the metal center, [RuCl 2 (PPh 3 ) 3 ] (2) was chosen for its ability to give a transCl 2 -cis-N 2 -cis-P 2 coordination environment around the Ru II center by reaction with a chelating phosphine and N-donor ligands. [7] Stirring equimolar amounts of 1, 2, and 1,3-bis(diphenylphosphino)propane (DPPP) in acetone at room temperature yielded the orange solid of 3 2 in good yield (87 %; Scheme 1).A single-crystal X-ray structure determination of 3 2 unambiguously revealed an interesting supramolecular association between two severely folded molecules of Ru II metallamacrocycle 3 (Figure 1). [8] The folded metallacycles 3, self-complementary monomers of 3 2 , are oriented orthogonally to each other. This orthogonal assembly s...