Nickel(II), Copper(II) and Zinc(II) Complexes of 9-[2- (Phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA), the 8-Aza Derivative of the Antiviral Nucleotide Analogue 9-[2-(Phosphonomethoxy)ethyl] adenine (PMEA). Quantification of Four Isomeric Species in Aqueous Solution

The acidity constants of the twofold protonated acyclic nucleotide analogue 9-[2-(phosphonomethoxy)- ethyl]-8-azaadenine, H2(9,8aPMEA)±, as well as the stability constants of the M(H;9,8aPMEA)+ and M(9,8aPMEA) complexes with the metal ions M2+ =Ni2+, Cu2+ or Zn2+, have been determined by potentiometric pH titrations in aqueous solution at I=0.1 M (NaNO3) and 25℃. The result for the release of the first proton from H2(9,8aPMEA)+ (pKa= 2.73), which originates from the (N1)H+ site, was confirmed by UV-spectrophotometric measurements. Application of previously determined straight-line plots of log KMM(R-PO3) versus PKH3(R-HPO3)' for simple phosph(on)ate ligands, R- PO-, where R represents a residue without an affinity for metal ions, proves that the primary binding site of 9,8aPMEA2- is the phosphonate group for all three metal ions studied. By stability constant comparisons with related ligands it is shown, in agreement with conclusions reached earlier for the Cu(PMEA) system [PMEA2-=dianion of 9-[2- (phosphonomethoxy)ethyl]adenine], that in total four different isomers are in equilibrium with each other, i.e. (i) an open isomer with a sole phosphonate coordination, M(PA)op, where PA2-=PMEA2-or 9,8aPMEA2-, (ii) an isomer with a 5-membered chelate involving the ether oxygen, M(PA)cl/o, (iii) an isomer which contains 5- and 7-membered chelates formed by coordination of the phosphonate group, the ether oxygen and the N3 site of the adenine residue, M(PA)cl/O/N3, and finally (iv) a macrochelated isomer involving N7, M(PA)cl/]N7. The Cu2+ systems of PMEA2- and 9,8aPMEA2- behave quite alike; the formation degrees for Cu(PA)op, CuM(PA)cl/O, Cu(PA)cl/O/N3 and Cu(PA)cl/N3 are approximately 16, 32, 45 and 7%, respectively, which shows that Cu(PA)cl/N7 is a minority species. In the Ni2+ and Zn2+ systems the open isomer is the dominating one followed by M(PA)cl/O, but there are indications that the other two isomers also occur to some extent

Quantification of isomeric equilibria formed by metal ion complexes of 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine (8,8aPMEA) and 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA). Derivatives of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)

The acidity constants of the two-fold protonated acyclic 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine, H2(9,8aPMEA)±, and its 8-isomer, 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine, H2(8,8aPMEA)±, both abbreviated as H2(PA)±, as well as the stability constants of their M(H;PA)+ and M(PA) complexes with the metal ions M2+=Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+ or Cd2+, have been determined by potentiometric pH titrations in aqueous solution at I=0.1M (NaNO3) and 25°C. Application of previously determined straight-line plots of log% MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! <![CDATA[% MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbb % f9v8qqaqFr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq % -He9q8qqQ8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaea % aakeaacaWGlbWaa0baaSqaaiaab2eacaqGOaGaaeOuaiaab2cacaqG % qbGaae4taWWaaSbaaeaacaqGZaaabeaaliaabMcaaeaacaqGnbaaaa % aa!4164! $$K_{{\text{M(R-PO}}_{\text{3}} {\text{)}}}^{\text{M}}$$ versus % MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! <![CDATA[% MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbb % f9v8qqaqFr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq % -He9q8qqQ8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaea % aakeaacaqGWbGaam4samaaDaaaleaacaqGibGaaeikaiaabkfacaqG % TaGaaeiuaiaab+eammaaBaaabaGaae4maaqabaWccaqGPaaabaGaae % isaaaaaaa!424D! $${\text{p}}K_{{\text{H(R-PO}}_{\text{3}} {\text{)}}}^{\text{H}}$$ for simple phosph(on)ate ligands, % MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! <![CDATA[% MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbb % f9v8qqaqFr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq % -He9q8qqQ8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaea % aakeaacaqGsbGaaeylaiaabcfacaqGpbWaa0baaSqaaiaaiodaaeaa % caaIYaGaeyOeI0caaaaa!3F15! $${\text{R-PO}}_3^{2-}$$, where R represents a residue without an affinity for metal ions, proves that for all M(PA) complexes a larger stability is observed than is expected for a sole phosphonate coordination of the metal ion. This increased stability is attributed to the formation of five-membered chelates involving the ether oxygen present in the aliphatic residue (% MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX! <![CDATA[% MathType!MTEF!2!1!+- % feaafeart1ev1aaatCvAUfeBSn0BKvguHDwzZbqefeKCPfgBGuLBPn % 2BKvginnfarmWu51MyVXgatuuDJXwAK1uy0HwmaeHbfv3ySLgzG0uy % 0Hgip5wzaebbnrfifHhDYfgasaacH8qrps0lbbf9q8WrFfeuY-Hhbb % f9v8qqaqFr0xc9pk0xbba9q8WqFfea0-yr0RYxir-Jbba9q8aq0-yq % -He9q8qqQ8frFve9Fve9Ff0dmeaabaqaciGacaGaaeqabaWaaeWaea % aakeaacaqGTaGaae4qaiaabIeadaWgaaWcbaGaaeOmaaqabaGccaqG % TaGaae4taiaab2cacaqGdbGaaeisamaaBaaaleaacaqGYaaabeaaki % aab2cacaqGqbGaae4tamaaDaaaleaacaqGZaaabaGaaeOmaiabgkHi % Taaaaaa!460C! $${\text{-CH}}_{\text{2}} {\text{-O-CH}}_{\text{2}} {\text{-PO}}_{\text{3}}^{{\text{2}}-}$$) of the ligands. The formation degrees of these chelates were calculated; they vary between about 13% for Ca(8,8aPMEA) and 71% for Cu(8,8aPMEA). The adenine residue has no influence on complex stability except in the Cu(9,8aPMEA) and Zn(9,8aPMEA) systems, where an additional stability increase attributable to the adenine residue is observed and equilibria between four different isomers exist. This means (1) an open isomer with a sole phosphonate coordination, M(PA)op, where PA2−=9,8aPMEA2−, (2) an isomer with a five-membered chelate involving the ether oxygen, M(PA)cl/O, (3) an isomer which contains five- and seven-membered chelates formed by coordination of the phosphonate group, the ether oxygen and the N3 site of the adenine residue, M(PA)cl/O/N3, and finally (4) a macrochelated isomer involving N7, M(PA)cl/N7. For Cu(9,8aPMEA) the formation degrees are 15, 30, 48 and 7% for Cu(PA)op, Cu(PA)cl/O, Cu(PA)cl/O/N3 and Cu(PA)cl/N7, respectively; this proves that the macrochelate involving N7 is a minority species. The situation for the Cu(PMEA) system, where PMEA2− represents the parent compound, i.e. the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine, is quite similar. The relationship between the antiviral activity of acyclic nucleoside phosphonates and the structures of the various complexes is discussed and an explanation is offered why 9,8aPMEA is biologically active but 8,8aPMEA is no

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

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

Synthetic approaches to "opened-ring" acyclic nucleoside phosphonates - novel type of antivirals

Diverse synthetic approaches to "opened-ring" acyclic nucleoside phosphonates - novel type of antivirals are described