Probing key coordination interactions: Configurationally restricted metal activated CXCR4 antagonists

Graeme McRobbie; Gina C. Valks; Christopher J. Empson; Abid Khan; Jon D. Silversides; Christophe Pannecouque; Erik De Clercq; Steven G. Fiddy; Adam J. Bridgeman; Nigel A. Young; Stephen J. Archibald

doi:10.1039/b705800d

Probing key coordination interactions: Configurationally restricted metal activated CXCR4 antagonists

Graeme McRobbie, Gina C. Valks, Christopher J. Empson, Abid Khan, Jon D. Silversides, Christophe Pannecouque, Erik De Clercq, Steven G. Fiddy, Adam J. Bridgeman, Nigel A. Young, Stephen J. Archibald^*

^*Corresponding author for this work

Imaging Chemistry & Biology

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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 EC₅₀ = 0.026 μM against HIV-1) than the non-constrained dicopper(ii) 1,1′-[1,4-phenylenebis(methylene)]-bis(1,4,8,11- tetraazacyclotetradecane) (average EC₅₀ = 0.047 μM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(ii) complex.

Original language	English
Pages (from-to)	5008-5018
Number of pages	11
Journal	Dalton Transactions
Issue number	43
DOIs	https://doi.org/10.1039/b705800d
Publication status	Published - 2007

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@article{7b2a65796e524a55a6d8a29f19e68d3a,

title = "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 EC50 = 0.026 μM against HIV-1) than the non-constrained dicopper(ii) 1,1′-[1,4-phenylenebis(methylene)]-bis(1,4,8,11- tetraazacyclotetradecane) (average EC50 = 0.047 μM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(ii) complex.",

author = "Graeme McRobbie and Valks, {Gina C.} and Empson, {Christopher J.} and Abid Khan and Silversides, {Jon D.} and Christophe Pannecouque and {De Clercq}, Erik and Fiddy, {Steven G.} and Bridgeman, {Adam J.} and Young, {Nigel A.} and Archibald, {Stephen J.}",

year = "2007",

doi = "10.1039/b705800d",

language = "English",

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journal = "Dalton Transactions",

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T2 - Configurationally restricted metal activated CXCR4 antagonists

AU - McRobbie, Graeme

AU - Valks, Gina C.

AU - Empson, Christopher J.

AU - Khan, Abid

AU - Silversides, Jon D.

AU - Pannecouque, Christophe

AU - De Clercq, Erik

AU - Fiddy, Steven G.

AU - Bridgeman, Adam J.

AU - Young, Nigel A.

AU - Archibald, Stephen J.

PY - 2007

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N2 - 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 EC50 = 0.026 μM against HIV-1) than the non-constrained dicopper(ii) 1,1′-[1,4-phenylenebis(methylene)]-bis(1,4,8,11- tetraazacyclotetradecane) (average EC50 = 0.047 μM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(ii) complex.

AB - 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 EC50 = 0.026 μM against HIV-1) than the non-constrained dicopper(ii) 1,1′-[1,4-phenylenebis(methylene)]-bis(1,4,8,11- tetraazacyclotetradecane) (average EC50 = 0.047 μM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(ii) complex.

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DO - 10.1039/b705800d

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C2 - 17992286

AN - SCOPUS:35548935013

SN - 1477-9226

SP - 5008

EP - 5018

JO - Dalton Transactions

JF - Dalton Transactions

IS - 43

ER -

Probing key coordination interactions: Configurationally restricted metal activated CXCR4 antagonists

Abstract

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