Probing key coordination interactions: configurationally restricted metal activated CXCR4 antagonists

Abstract

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.

Aspartate‐Based CXCR4 Chemokine Receptor Binding of Cross‐Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes

“…The most potent compounds are [Cu 3 (OAc)] + and [Zn 4 (OAc)] + with [Zn 6 (OAc)] + and [Zn 5 (OAc)] + also highly active. The IC 50 values are about 10 n m in the CXCL12 binding inhibition assay and 50 n m in the signaling assay, showing that, in these assays, they are of similar potency to AMD3100 and approach the activity of the high affinity bismacrocyclic metal complexes that we have developed (e.g, with chelator 8 ; for the structure of this ligand, please see Figure below) …”

“…DFT calculations have previously been reported on copper(II) cross‐ and side‐bridged derivatives, showing a geometry‐optimised, five‐coordinate, distorted square‐based pyramidal complex for both, with cross‐bridged exhibiting shorter Cu−O acetate bond lengths and increased stability compared to cross‐bridged derivatives . Because of the systematic differences in Zn 2+ coordination of acetate dependent on the presence or absence of the macrocyclic cross‐bridge in the structures discussed above, we wanted to further examine this phenomenon.…”

Review: Properties and chemical reactivity of metallo phthalocyanine and tetramethylbenzoannulene complexes grafted into a polymer backbone

“…In this role, polyazamacrocycles have been extensively studied [11][12][13][14][15][16] because they are able to coordinate divalent metal cations, such as Ni 2+ or Cu 2+ , by displacing the amide protons. The complexes have many applications in catalysis [23], molecular machines, oxygen uptake [18,19], medicine [18], as antiviral agents [25][26][27], and can also be studied as biological models for metalloproteins [28] in a polymeric environment. For example, the structural features of the macrocycles and the unique radiophysical properties of copper radioisotopes have led to their potential usefulness in diagnostic and/or therapeutic applications [29].…”

Synthesis, structural studies, and oxidation catalysis of the manganese(II), iron(II), and copper(II) complexes of a 2-pyridylmethyl pendant armed side-bridged cyclam

“…“side-bridged”) have been known since 1980. [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] The additional bridge provides rigidity, configurational selectivity, and kinetic stability and has been synthetically put in place by several different methods. [17] [18] [19] [20] [21] Like other cyclam ligands, additional utility can be added by addition of pendant arms, which have included in Scheme 1, structure 1 : R and/or R′ = H, [17] [21] Me, [19] Et, [20] Bz, [19] [23] [22]Bz- p -NO 2 , [22] [25]Bz- p -NH 2 , [22] CH 2 CO 2 H, [24] [26]CH 2 PO 3 H [25] [26] and others.…”

“…[41] We raised the yields of the monoalkyl salt 5 to 66% by addition of KI and increasing the temperature to reflux over 6 days. Typical reduction conditions [23] gave 3 in good yield. Metal complexation with anhydrous metal chlorides in dry solvents under nitrogen gave adequate yields of the desired complexes.…”