Timothy J. Hubin

Template routes to interlocked molecular structures and orderly molecular entanglements

Abstract This review discusses the synthesis of mechanically interlocked molecules where templates orient the reactants to produce permanent structures as the result of new linkages. An introduction outlines the concepts and opportunities of the field, paying special attention to the components of chemical templates. Next, the chemical template types most successfully applied to the synthesis of new interlocked molecular structures, metal ion templates, hydrogen bonded templates, cyclodextrin templates, and π-donor π-acceptor templates, are described. The progress each template type has made towards the goal of true polymeric interlocked structures is noted. The conclusion summarizes the current state of the field and points out new directions that appear ripe for future exploration.

Synthesis and coordination chemistry of topologically constrained azamacrocycles

Abstract Bridging superstructures added to small azamacrocycles, through the accompanying additional topological constraint, enhance the characteristic that makes azamacrocycles indispensable ligands for transition metal coordination including biomimetic chemistry: high complex stability. This review begins by briefly revisiting the coordination chemistry concepts leading to this advantage over less topologically complex ligands. Then, it details the approaches used to synthesize such bridged azamacrocycles, including direct organic synthesis, the use of templates, protection/deprotection chemistry, and various condensation reactions. The example of a specific ligand type and its transition metal complexes, which are useful for biomimetic applications, illustrates the potential of the field and lead to some general conclusions.

Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes

A new copper(II) containing bis-macrocyclic CXCR4 chemokine receptor antagonist is shown to have improved binding properties to the receptor protein in comparison to the drug AMD3100 (Plerixafor, Mozobil). The interaction of the metallodrug has been optimized by using ultrarigid chelator units that offer an equatorial site for coordination to the amino acid side chains of the protein. Binding competition assays with anti-CXCR4 antibodies show that the new compound stays bound longer and it has improved anti-HIV potency in vitro (EC(50) = 4.3 nM). X-ray structural studies using acetate as a model for carboxylate amino acid side chains indicate the nature of the coordination interaction.

Synthesis, structure, and stability in acid of copper(II) and zinc(II) complexes of cross-bridged tetraazamacrocycles

New copper(II) and zinc(II) complexes of cross-bridged tetraazamacrocyclic ligands derived from 1,4,8,11-tetraazacyclotetradecane (cyclam), 1,4,7,10-tetraazacyclotridecane ([13]aneN4), and 1,4,7,10-tetraazacyclododecane (cyclen) have been synthesized. The X-ray crystal structures of the two cyclen-derived complexes have been determined and show both metal ions to be in distorted octahedral environments with the ligand in a cis -folded conformation. The bridged-ligand complexes are remarkably stable kinetically under harsh acidic conditions, as seen from their dissociation reactions. The electrochemical and spectroscopic properties of the Cu 2 complexes have also been investigated. # 2003 Elsevier Science B.V. All rights reserved.

Synthesis and X-ray crystal structures of iron(II) and manganese(II) complexes of unsubstituted and benzyl substituted cross-bridged tetraazamacrocycles

Abstract The Mn2+ and Fe2+ complexes of the cross-bridged tetraazamacrocyclic ligands, 4,11-dibenzyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), 4,10-dibenzyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (2), 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3), and 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (4) provide new compounds of these elements for fundamental studies and applications. These unsubstituted and benzyl substituted derivatives were prepared for comparison of their structures and properties with the known catalytically active dimethyl cross-bridged ligand complexes, which are especially notable for their exceptional kinetic stabilities and redox activity. The X-ray crystal structures of five complexes demonstrate that the ligands enforce a distorted octahedral geometry on the metals with two cis sites occupied by labile ligands. The Fe2+ complexes of the unsubstitued ligands form μ-oxo dimers upon exposure to air, which have also been structurally characterized. Cyclic voltammetry of the monomeric complexes shows reversible redox processes for the M3+/M2+ couples, which are sensitive to solvent, ring size, and ring substitution.

Influence of calcium(II) and chloride on the oxidative reactivity of a manganese(II) complex of a cross-bridged cyclen ligand

Available data from different laboratories have confirmed that both Ca(2+) and Cl(-) are crucial for water oxidation in Photosystem II. However, their roles are still elusive. Using a manganese(II) complex having a cross-bridged cyclen ligand as a model, the influence of Ca(2+) on the oxidative reactivity of the manganese(II) complex and its corresponding manganese(IV) analogue were investigated. It has been found that adding Ca(2+) can significantly improve the oxygenation efficiency of the manganese(II) complex in sulfide oxidation and further accelerate the oxidation of sulfoxide to sulfone. Similar improvements have also been observed for Mg(2+), Sr(2+), and Ba(2+). A new monomeric manganese(IV) complex having two cis-hydroxide ligands has also been isolated through oxidation of the corresponding manganese(II) complex with H2O2 in the presence of NH4PF6. This rare cis-dihydroxomanganese(IV) species has been well characterized by X-ray crystallography, electrochemistry, electron paramagnetic resonance, and UV-vis spectroscopy. Notably, using the manganese(IV) complex as a catalyst demonstrates higher activity than the corresponding manganese(II) complex, and adding Ca(2+) further improves its catalytic efficiency. However, adding Cl(-) decreases its catalytic activity. In electrochemical studies of manganese(IV) complexes with no chloride ligand present, adding Ca(2+) positively shifted the redox potential of the Mn(IV)/Mn(III) couple but negatively shifted its Mn(V)/Mn(IV) couple. In the manganese(II) complex having a chloride ligand, adding Ca(2+) shifted both the Mn(IV)/Mn(III) and Mn(V)/Mn(IV) couples in the negative direction. The revealed oxidative reactivity and redox properties of the manganese species affected by Ca(2+) and Cl(-) may provide new clues to understanding their roles in the water oxidation process of Photosystem II.

Synthesis, characterization, and X-ray crystal structures of cobalt(II) and cobalt(III) complexes of four topologically constrained tetraazamacrocycles

The high spin Co2+ complexes of 4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), 4,10-dimethyl-1,4,7,10-tetraazabicyclo[6.5.2]pentadecane (2), 4,10-dimethyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (3), and racemic-4,5,7,7,11,12,14,14-octamethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4) have been synthesized and characterized by X-ray crystallography. The Co(III) complexes of 1-3 were also prepared by the chemical oxidation of the Co(II) complexes. The X-ray crystal structures of Co(1)Cl-2, Co(3)Cl-2, and [Co(3)Cl-2]PF6 demonstrate that the ligands enforce a distorted octahedral geometry on Co(II) and Co(III) with two cis sites occupied by chloro ligands. In contrast, the Co(II) complex of 4 is five-coordinate with trigonal bipyramidal geometry. The methyl groups substituted on the carbon atoms of ligand 4 define a shallow cavity, allowing only one chloride ligand to bind to the chelated metal ion. This difference in coordination geometry causes Co(4)Cl+ to be much more difficult to oxidize (E-1/2 = 1.176 V vs. SHE) than the octahedral Co(II) complexes of 1-3 (E-1/2 from -0.157 to 0.173 V vs. SHE). The Co(III) complexes of 1-3 have three absorbances in their electronic spectra, while typical cis-Co(III)N4X2 complexes have only two. This additional splitting of energy states is attributed to the increased distortion from octahedral resulting from the short ethylene cross-bridge on the macrobicyclic ligands

IL-24 Inhibits Lung Cancer Cell Migration and Invasion by Disrupting The SDF-1/CXCR4 Signaling Axis

Background The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis and is molecular target for therapy. In the present study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4 antagonists was investigated. Methods Human H1299, A549, H460 and HCC827 lung cancer cell lines were used in the present study. The H1299 lung cancer cell line was stably transfected with doxycycline-inducible plasmid expression vector carrying the human IL-24 cDNA and used in the present study to determine the inhibitory effects of IL-24 on SDF-1/CXCR4 axis. H1299 and A549 cell lines were used in transient transfection studies. The inhibitory effects of IL-24 on SDF1/CXCR4 and its downstream targets were analyzed by quantitative RT-PCR, western blot, luciferase reporter assay, flow cytometry and immunocytochemistry. Functional studies included cell migration and invasion assays. Principal Findings Endogenous CXCR4 protein expression levels varied among the four human lung cancer cell lines. Doxycycline-induced IL-24 expression in the H1299-IL24 cell line resulted in reduced CXCR4 mRNA and protein expression. IL-24 post-transcriptionally regulated CXCR4 mRNA expression by decreasing the half-life of CXCR4 mRNA (>40%). Functional studies showed IL-24 inhibited tumor cell migration and invasion concomitant with reduction in CXCR4 and its downstream targets (pAKTS473, pmTORS2448, pPRAS40T246 and HIF-1α). Additionally, IL-24 inhibited tumor cell migration both in the presence and absence of the CXCR4 agonist, SDF-1. Finally, IL-24 when combined with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory activity on tumor cell migration. Conclusions IL-24 disrupts the SDF-1/CXCR4 signaling pathway and inhibits lung tumor cell migration and invasion. Additionally, IL-24, when combined with CXCR4 inhibitors exhibited enhanced anti-metastatic activity and is an attractive therapeutic strategy for lung metastasis.

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn(2+) complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn(2+). Few of the Cu(2+) and Fe(2+) complexes also showed improvement in activity but Ni(2+), Co(2+) and Zn(2+) complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development.

CXCR4 chemokine receptor antagonists: nickel(II) complexes of configurationally restricted macrocycles

Tetraazamacrocyclic complexes of transition metals provide useful units for incorporating multiple coordination interactions into a single protein binding molecule. They can be designed with available sites for protein interactions via donor atom-containing amino acid side chains or labile ligands, such as H(2)O, allowing facile exchange. Three configurationally restricted nickel(II) cyclam complexes with either one or two macrocyclic rings were synthesised and their ability to abrogate the CXCR4 chemokine receptor signalling process was assessed (IC(50) = 8320, 194 and 14 nM). Analogues were characterised crystallographically to determine the geometric parameters of the acetate binding as a model for aspartate. The most active nickel(II) compound was tested in several anti-HIV assays against representative viral strains showing highly potent EC(50) values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC(50) > 125 μM).