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Extent of intramolecular π stacks in aqueous solution in mixed-ligand copper(II) complexes formed by heteroaromatic amines and the anticancer and antivirally active 9-[2-phosphonomethoxy)ethyl]guanine (PMEG).✩ a comparison with related acyclic nucleotide analogues
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Blindauer, Claudia A., Sigel, Astrid, Operschall, Bert P. , Griesser, Rolf, Holý, Antonín and Sigel, Helmut (2016) Extent of intramolecular π stacks in aqueous solution in mixed-ligand copper(II) complexes formed by heteroaromatic amines and the anticancer and antivirally active 9-[2-phosphonomethoxy)ethyl]guanine (PMEG).✩ a comparison with related acyclic nucleotide analogues. Polyhedron, 103 (Part B). pp. 248-260. doi:10.1016/j.poly.2015.02.022 ISSN 0277-5387.
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Official URL: http://dx.doi.org/10.1016/j.poly.2015.02.022
Abstract
The acyclic nucleoside phosphonate (ANP2–
) 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG) is
anticancer and antivirally active. The acidity constants of the threefold protonated H3(PMEG)+
were determined by potentiometric pH titrations (aq. sol.; 25°C; I = 0.1 M, NaNO3). Under the
same conditions and by the same method, the stability constants of the binary Cu(H;PMEG)+ and
Cu(PMEG) complexes as well as those of the ternary ones containing a heteroaromatic N ligand
(Arm), that is, of Cu(Arm)(H;PMEG)+ and Cu(Arm)(PMEG), where Arm = 2,2'-bipyridine
(Bpy) or 1,10-phenanthroline (Phen), were measured. The corresponding equilibrium constants,
taken from our earlier work for the systems with 9-[2-(phosphonomethoxy)ethyl]adenine
(PMEA) and 9-[2-(phosphonomethoxy)ethyl]-2,6-diamino-purine (PMEDAP) as well as those
for Cu(PME) and Cu(Arm)(PME), where PME2– = (phosphonomethoxy)ethane =
(ethoxymethyl)phosphonate, were used for comparisons. These reveal that in the
monoprotonated ternary Cu(Arm)(H;PE)+ complexes, the proton and Cu(Arm)2+ are at the
phosphonate group; the ether oxygen of the -CH2-O-CH2-P(O) 2
! (OH) residue also participates to
some extent in Cu(Arm)2+ coordination. Furthermore, the coordinated Cu(Arm)2+ forms a bridge
with the purine moiety undergoing π-π stacking which is more pronounced with H·PMEDAP–
than with H·PMEA–
. Most intense is π stack formation (st) with the guanine residue of
H·PMEG–
; here the bridged form Cu(Arm)(H·PMEG) st
+ occurs next to an open (op), unbridged
(binary) stack, formulated as Cu(Arm)2+/(H·PMEG) op
! . – The unprotonated and neutral ternary
Cu(Arm)(PE) complexes are considerably more stable than the corresponding Cu(Arm)(R-PO3)
species, where R-PO3
2! represents a phosph(on)ate ligand with a group R that is unable to
participate in any intramolecular interaction. The observed stability enhancements are mainly
due to intramolecular stack formation (st) between the aromatic rings of Arm and the purine
residue in the Cu(Arm)(PE) complexes and also, to a smaller extent, to the formation of fivemembered
chelates involving the ether oxygen of the -CH2-O-CH2-PO 3
2! residue (cl/O) of the
PE2– species. The quantitative analysis of the intramolecular equilibria reveals three structurally
different Cu(Arm)(PE) isomers; e.g., of Cu(Phen)(PMEG) ca. 1.1% exist as Cu(Phen)(PMEG)op,
3.5% as Cu(Phen)(PMEG)cl/O, and 95% as Cu(Phen)(PMEG)st. Comparison of the various
3
formation degrees reveals that within a given Cu(Arm)(PE) series the stacking tendency
decreases in the order PMEG2– ≥ PMEDAP2– > PMEA2–
. Furthermore, stacking is more
pronounced in the acyclic Cu(Arm)(PE) complexes compared with that in the Cu(Arm)(NMP)
species, where NMP2– = corresponding parent (2'-deoxy)nucleoside 5'-monophosphate. Here is
possibly one of the reasons for the biological activity of the ANPs. One is tempted to speculate
that the pronounced stacking tendency of PMEG2–
, together with a different H-bonding pattern,
leads to enhanced binding in the active site of nucleic acid polymerases, thus being responsible
for the pronounced anticancer and antiviral activity of PMEG.
Item Type: | Journal Article | ||||||||
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Subjects: | Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
Library of Congress Subject Headings (LCSH): | Antiviral agents, Chemistry, Inorganic, Virus diseases -- Chemotherapy | ||||||||
Journal or Publication Title: | Polyhedron | ||||||||
Publisher: | Pergamon | ||||||||
ISSN: | 0277-5387 | ||||||||
Official Date: | January 2016 | ||||||||
Dates: |
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Volume: | 103 | ||||||||
Number: | Part B | ||||||||
Page Range: | pp. 248-260 | ||||||||
DOI: | 10.1016/j.poly.2015.02.022 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||
Date of first compliant deposit: | 14 April 2016 | ||||||||
Date of first compliant Open Access: | 27 February 2017 |
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