Configurations of metallocyclams and relevance to anti-HIV activity

Hunter, Tina M.; Paisey, Stephen J.; Park, Hye-Seo; Cleghorn, Laura A. T.; Parkin, Andrew; Parsons, Simon; Sadler, Peter J.

doi:10.1016/j.jinorgbio.2003.10.018

Cited by 47 publications

(35 citation statements)

References 37 publications

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“…1 On metal complex formation, the tetra-aza macrocyclic rings in AMD3100 show multiple configurations in solution. 2 Configurationally fixed analogues would have the advantage of presenting only one configuration in solution for coordinate bond formation on binding to the protein. Our study aims to produce a series of configurationally fixed complexes and show the key importance of the coordination interaction for drug binding.…”

Section: Amd3100 (The Octa Hcl Salt Of 1-1′-[14-phenylenebis-(methylmentioning

confidence: 99%

Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists

et al. 2006

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A zinc(II) containing configurationally restricted analogue of bismacrocyclic cyclam-type CXCR4 chemokine receptor antagonists has been synthesized and shown to adopt only one configuration in solution. The single crystal X-ray structure reveals favorable binding to acetate via a bidentate chelation that can be related to the proposed interaction with aspartate on the receptor protein surface. The zinc(II) complex is highly active against HIV infection in vitro. AMD3100 (the octa HCl salt of 1-1′-[1,4-phenylenebis-(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane)), Figure 1c, is a drug that interacts with a cell surface protein (CXCR4) via hydrogen bonding interactions or more effectively as the metal complex via coordinate bonds with aspartate residues. 1 On metal complex formation, the tetra-aza macrocyclic rings in AMD3100 show multiple configurations in solution. 2 Configurationally fixed analogues would have the advantage of presenting only one configuration in solution for coordinate bond formation on binding to the protein. Our study aims to produce a series of configurationally fixed complexes and show the key importance of the coordination interaction for drug binding. We also wish to validate the general strategy of configurational fixing as a route to improve the activity of metal-containing drugs.The CXCR4 chemokine receptor is a seven-helix transmembrane G-protein coupled receptor with multiple critical functions in both normal and pathological physiology. It is a member of the family of 18 recognized chemokine receptors and has a sole natural ligand (CXCL12). 3 Synthetic small molecule antagonists exist, including AMD3100, and have been shown to have both a high binding specificity and an effective inhibitory action against a number of disease states. 4,5 For example, in vitro assays show that AMD3100 inhibits infection by the human immunodeficiency virus (HIV-1 and HIV-2) at micromolar concentrations. 6 It has been demonstrated that formation of metal complexes and aza-macrocyclic ring configuration may have major effects on AMD3100-protein interactions. 1,2,[7][8][9] In particular, it has been suggested that zinc(II) could play a key role in the biological activity of the bicyclam derivatives. 10,11 In an attempt to rationalize the effects of cyclam configuration and to produce new specific antagonists for CXCR4, we have successfully synthesized a configurationally fixed bismacrocyclic compound and its zinc(II) complex. The solution and solid-state properties of the zinc(II) complex were investigated via high field NMR (800 MHz) and X-ray crystallography. The inhibitory effect on infection by HIV-1 and HIV-2 in MT-4 cells is also presented for both the chelator, 4 ((5-5′-[1,4-phenylenebis(methylene)]-bis (1,5,8,12-tetraazabicyclo[10.2.2]hexadecane)), and the complex Zn 2 4(OAc) 4 .There are six possible configurations that a cyclam ring can adopt on complexation to a metal ion, as defined by Bosnich and co-workers and shown in Figure 1b, where trans-III is generally the most thermodyn...

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Section: Amd3100 (The Octa Hcl Salt Of 1-1′-[14-phenylenebis-(methylmentioning

confidence: 99%

Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists

et al. 2006

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“…1, 3-Diones and its metal complexes appear very promising for potential use as antibacterial agents due to their other biological properties [14][15][16][17] . There is continue interest in synthesizing 1, 3-diones 4(L A -L B ) and its metal complexes 5(a-e) because of their potential applications, applied sciences and importance area of coordination chemistry [18][19][20][21] .…”

Section: Research Articlementioning

confidence: 99%

Synthesis, Spectral Characterization and Biological Screening of Potentially Active 1, 3-Diones and its Transition Metal Complexes

2016

Chem Sci Trans

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1-(2-Hydroxyphenyl)-3-propane-1, 3-diones 4(L A -L B ) and its metal complexes 5(a-e) have been newly synthesized from substituted 2-hydroxyacetophenones 1(A-B) and aromatic acids 2(A-B) under ultrasound irradiation method at low temperature. These compounds were characterized by FT-IR, UV-Vis., 1 H-NMR, 13 C-NMR, mass spectroscopy and magnetic measurement. The stoichiometry of the complexes was found 1:2 (metal:ligand). The physicochemical data suggested octahedral geometry for all the complexes. The ligands 4(L A -L B ) and their metal complexes 5(a-e) were screened for in vitro antibacterial activity against S. aureus, B. subtilis, E. coli and P. aeruginosa compared with tetracycline and chloramphenicol as a standard drugs. The results are in good agreement with respect to activity of free ligand and its metal complexes. Reactions under ultrasonic irradiation had improved yield.

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“…Studies of the Cambridge Structural Database (CSD) show that the trans-III configuration is the most common configuration in the solid state. [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.…”

Section: Nia C H T U N G T R E N N U N G (Cyclam)-a C H T U N G T R Ementioning

confidence: 99%

Configurations of Nickel–Cyclam Antiviral Complexes and Protein Recognition

Hunter

McNae

Simpson

et al. 2006

Chemistry A European J

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Nickel(II)–xylylbicyclam is a potent anti‐HIV agent and binds strongly to the CXCR4 co‐receptor. We have investigated configurational equilibria of NiII–cyclam derivatives, since these are important for receptor recognition. Crystallographic studies show that both trans and cis configurations are readily formed: [Ni(cyclam)(OAc)2]⋅H2O adopts the trans‐III configuration with axial monodentate acetates, as does [Ni(benzylcyclam)(NO3)2] with axial nitrate ligands, whereas [Ni(benzylcyclam)(OAc)](OAc)⋅2 H2O has an unusual folded cis‐V configuration with NiII coordination to bidentate acetate. UV/Vis and NMR studies show that the octahedral trans‐III configuration slowly converts to square‐planar trans‐I in aqueous solution. For NiII–xylylbicyclam, a mixture of cis‐V and trans‐I configurations was detected in solution. X‐ray diffraction studies showed that crystals of lysozyme soaked in NiII–cyclam or NiII2–xylylbicyclam contain two major binding sites, one involving NiII coordination to Asp101 and hydrophobic interactions between the cyclam ring and Trp62 and Trp63, and the second hydrophobic interactions with Trp123. For NiII–cyclam bound to Asp101, the cis‐V configuration predominates.

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Configurations of metallocyclams and relevance to anti-HIV activity

Cited by 47 publications

References 37 publications

Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists

Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists

Synthesis, Spectral Characterization and Biological Screening of Potentially Active 1, 3-Diones and its Transition Metal Complexes

Configurations of Nickel–Cyclam Antiviral Complexes and Protein Recognition

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