Selective Recognition of Configurational Substates of Zinc Cyclam by Carboxylates: Implications for the Design and Mechanism of Action of Anti‐HIV Agents

Abstract

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)](n)(CH(3)OH)(2n) and [Zn(cyclam)(H(2)O)(2)](OAc)(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.

Tuning the Photophysical Behavior of Luminescent Cyclam Derivatives by Cation Binding and Excited State Redox Potential

“…Despite repeated efforts utilizing several chromatographic techniques, these isomers were not separable, possibly due to kinetic lability of the bound metal ion. It has been previously observed 34 that crystallized Zn(II) complexes of the structurally related cyclam macrocycle, with a known configuration of N-donors, rapidly isomerize to give an equilibrium distribution when redissolved, and it is likely that a similar situation applies in this case. As such, the decay behavior of both Zn(II) complexes is in accord with the 1 H NMR Zn(II) complexation titrations, which demonstrated the appearance of two differing methylene linker resonances.…”

Configurations of Nickel–Cyclam Antiviral Complexes and Protein Recognition

“…It is known that only the trans-I and trans-III configurations give rise to three pairs of signals in the 2D [ 1 H, 13 C] HSQC spectrum, therefore Ni II cyclam acetate must adopt one of these configurations. [11] Since squareplanar Ni II is a better fit for the cavity in trans-I cyclam, it is concluded that diamagnetic Ni II cyclam adopts the trans-I configuration in the present case.…”

“…[10] It has been shown that trans-III complexes of zinccyclam complexes (with acetate, phthalate, perchlorate or chloride as counterions) equilibrate over a period of hours to form mixtures of cis-V, trans-I and trans-III isomers. [11,12] Acetate, in particular, can induce formation of the cis-V configuration, and the most prominent adduct of Zn II 2 -xylylbicyclam in the presence of acetate adopts cis-V/trans-I configurations. [12] Metal complexes of xylylbicyclam appear to bind to the carboxylate groups of Asp262, Glu288 and Asp171 of CXCR4.…”

“…This is in contrast to the highly active zinc complex. [11,12] Acetate readily induces formation of cis-V configurations of zinc-cyclam and zinc-xylylbicyclam complexes. It is known that Ni II but not Zn II has a strong tendency to form square-planar complexes.…”

“…In contrast, aqueous solutions of zinc-cyclam perchlorate and zinc-cyclam chloride complexes consist mainly of the trans-III configuration, while carboxylato complexes predominantly adopt the cis-V configuration. [11] The nickel-benzylcyclam nitrate complex 6 is unusual in that nitrate is involved in direct binding to the metal. Nitrate normally has a weak affinity for metals, and there are few examples of Ni II complexes containing coordinated nitrate (none in the CSD).…”