CXCR4 chemokine receptor antagonists: Nickel(ii) complexes of configurationally restricted macrocycles

Rachel Smith; Dana Huskens; Dirk Daelemans; Ryan E. Mewis; Courtney D. Garcia; Amy N. Cain; Ta Rynn N.Carder Freeman; Christophe Pannecouque; Erik De Clercq; Dominique Schols; Timothy J. Hubin; Stephen J. Archibald

doi:10.1039/c2dt31137b

CXCR4 chemokine receptor antagonists: Nickel(ii) complexes of configurationally restricted macrocycles

Rachel Smith, Dana Huskens, Dirk Daelemans, Ryan E. Mewis, Courtney D. Garcia, Amy N. Cain, Ta Rynn N.Carder Freeman, Christophe Pannecouque, Erik De Clercq, Dominique Schols, Timothy J. Hubin^*, Stephen J. Archibald

^*Corresponding author for this work

Imaging Chemistry & Biology

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

Abstract

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 ₂O, 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 (IC₅₀ = 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 EC₅₀ values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC₅₀ > 125 μM).

Original language	English
Pages (from-to)	11369-11377
Number of pages	9
Journal	Dalton Transactions
Volume	41
Issue number	37
DOIs	https://doi.org/10.1039/c2dt31137b
Publication status	Published - 2012

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title = "CXCR4 chemokine receptor antagonists: Nickel(ii) complexes of configurationally restricted macrocycles",

abstract = "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 2O, 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 (IC50 = 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 EC50 values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC50 > 125 μM).",

author = "Rachel Smith and Dana Huskens and Dirk Daelemans and Mewis, {Ryan E.} and Garcia, {Courtney D.} and Cain, {Amy N.} and Freeman, {Ta Rynn N.Carder} and Christophe Pannecouque and Clercq, {Erik De} and Dominique Schols and Hubin, {Timothy J.} and Archibald, {Stephen J.}",

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doi = "10.1039/c2dt31137b",

language = "English",

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journal = "Dalton Transactions",

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T1 - CXCR4 chemokine receptor antagonists

T2 - Nickel(ii) complexes of configurationally restricted macrocycles

AU - Smith, Rachel

AU - Huskens, Dana

AU - Daelemans, Dirk

AU - Mewis, Ryan E.

AU - Garcia, Courtney D.

AU - Cain, Amy N.

AU - Freeman, Ta Rynn N.Carder

AU - Pannecouque, Christophe

AU - Clercq, Erik De

AU - Schols, Dominique

AU - Hubin, Timothy J.

AU - Archibald, Stephen J.

PY - 2012

Y1 - 2012

N2 - 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 2O, 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 (IC50 = 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 EC50 values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC50 > 125 μM).

AB - 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 2O, 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 (IC50 = 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 EC50 values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC50 > 125 μM).

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DO - 10.1039/c2dt31137b

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AN - SCOPUS:84872019230

SN - 1477-9226

VL - 41

SP - 11369

EP - 11377

JO - Dalton Transactions

JF - Dalton Transactions

IS - 37

ER -

CXCR4 chemokine receptor antagonists: Nickel(ii) complexes of configurationally restricted macrocycles

Abstract

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