Ross, Allison, Soares, Dinesh C., Covelli, Danielle, Pannecouque, Christophe, Budd, Laura, Collins, Anna, Robertson, N. (Neil), Parsons, S. (Simon), De Clercq, Erik, Kennepohl, Pierre and Sadler, P. J.. (2010) Oxovanadium(IV) cyclam and bicyclam complexes : potential CXCR4 receptor antagonists. Inorganic Chemistry, Vol.49 (No.3). pp. 1122-1132. ISSN 0020-1669

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Abstract

Metal complexation can have a major influence on the antiviral and coreceptor binding properties of cyclam and bicylam macrocycles. We report the synthesis of the vanadyl cyclam complexes [(VO)-O-(IV)(cyclam)SO4] (1) and [(VO)-O-(IV)(cyclam)CI]Cl (2) and the analogous xylylbicyclam sulfato (3) and chlorido (4) complexes. The X-ray crystal structures of 1.1.33CH(3)OH and 2 center dot CH3OH center dot 1.5H(2)O show short V=O bonds (1.6093(19) and 1.599(3) angstrom. respoctively) with monodentate sulfate H-bonded to ring NH groups for 1, but a long V-Cl bond (2.650(12) A) for 2. The solid-state structures of 3 and 4 were compared to those of 1 and 2 using vanadium K-edge extended X-ray absorption fine structure (EXAFS) data. These suggested that complex 4 was oligomeric and contained bridging chlorido ligands. Electron paramagnetic resonance (EPR) studies suggested that the SO42- (from 1) and Cl- (from 2) ligands are readily substituted by water in solution, whereas these remain partially bound for the V-IV xylylbicyclam complexes 3 and 4. The vanadyl xylylbicyclam complexes were highly active against HIV-1 (IIIB)) and HIV-2 (ROD) strains with IC50 values in the range 1-5 mu M for 3 and 0.1-0.3 mu M for 4; in contrast the vanadyl cyclam complexes 1 and 2 were inactive. The factors that contribute to the activity of these complexes are discussed. Studies of vanadyl cyclam docked into a model of the human CXCR4 coreceptor revealed that the coordination of vanadium to the carboxylate of Asp171 may be accompanied by H-bonding to the macrocycle and an attractive V=O center dot center dot center dot H interaction involving the backbone Trp195 alpha-carbon proton of CXCR4. In addition, hydrophobic interactions with Trp195 are present. Both ring configuration and the xylyl linker may play roles in determining the higher activity of the bicyclam complexes.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Macrocyclic compounds, Receptor-ligand complexes
Journal or Publication Title:	Inorganic Chemistry
Publisher:	American Chemical Society
ISSN:	0020-1669
Date:	1 February 2010
Volume:	Vol.49
Number:	No.3
Number of Pages:	11
Page Range:	pp. 1122-1132
Identification Number:	10.1021/ic9020614
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), National Institutes of Health (U.S.) (NIH), United States. Dept. of Energy, National Center for Research Resources (U.S.). Biomedical Technology, Engineering and Physical Sciences Research Council (EPSRC), University of Manchester, National Center for Research Resources (U.S.) (NCRR)
URI:	http://wrap.warwick.ac.uk/id/eprint/16551

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