Ternary Copper(II) Complexes in Solution Formed With 8-Aza Derivatives of the Antiviral Nucleotide Analogue 9-[2-(Phosphonomethoxy)Ethyl]adenine (PMEA)

The stability constants of the mixed-ligand complexes formed between Cu(Arm)2+, where Arm = 2,2′-bipyridine (Bpy) or 1,10-phenanthroline (Phen), and the dianions of 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA) and 8-[2-(phosphonomethoxy)ethyl]8-azaadenine (8,8aPMEA) (both also abbreviated as PA2-) were determined by potentiometric pH titrations in aqueous solution (25 °C; I = 0.1 M, NaNO3). All four ternary Cu(Arm)(PA) complexes are considerably more stable than 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 kind of interaction within the complexes. The increased stability is attributed to intramolecular stack formation in the Cu(Arm)(PA) complexes and also to the formation of 5-membered chelates involving the ether oxygen present in the -CH2-O-CH2-PO3 2- residue of the azaPMEAs. A quantitative analysis of the intramolecular equilibria involving three structurally different Cu(Arm)(PA) species is carried out. For example, about 5% of the Cu(Bpy)(8,8aPMEA) system exist with the metal ion solely coordinated to the phosphonate group, 14% as a 5-membered chelate involving the -CH2-O-CH-2-PO3 2- residue, and 81% with an intramolecular stack between the 8-azapurine moiety and the aromatic rings of Bpy. The results for the other systems are similar though with Phen a formation degree of about 90% for the intramolecular stack is reached. The existence of the stacked species is also proven by spectrophotometric measurements. In addition, the Cu(Arm)(PA) complexes may be protonated, leading to Cu(Arm)(H;PA)+ species for which it is concluded that the proton is located at the phosphonate group and that the complexes are mainly formed by a stacking adduct between Cu(Arm)2+ and H(PA)-. Conclusions regarding the biological properties of these azaPMEAs are shortly indicated

Synthesis of purine N-9-[2-hydroxy-3-O-(phosphonomethoxy)propyl] derivatives and their side-chain modified analogs as potential antimalarial agents

6-Oxopurine acyclic nucleoside phosphonates (ANPs) have been shown to be potent inhibitors of hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT), a key enzyme of the purine salvage pathway in human malarial parasites. These compounds also exhibit antimalarial activity against parasites grown in culture. Here, a new series of ANPs, hypoxanthine and guanine 9-[2-hydroxy-3-(phosphonomethoxy)propyl] derivatives with different chemical substitutions in the 2′-position of the aliphatic chain were prepared and tested as inhibitors of Plasmodium falciparum (Pf) HGXPRT, Plasmodium vivax (Pv) HGPRT and human HGPRT. The attachment of an hydroxyl group to this position and the movement of the oxygen by one atom distal from N in the purine ring compared with 2-(phosphonoethoxy)ethyl hypoxanthine (PEEHx) and 2-(phosphonoethoxy)ethyl guanine (PEEG) changes the affinity and selectivity for human HGPRT, PfHGXPRT and PvHGPRT. This is attributed to the differences in the three-dimensional structure of these inhibitors which affects their mode of binding. A novel observation is that these molecules are not always strictly competitive with 5-phospho-α-d-ribosyl-1-pyrophosphate. 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]hypoxanthine (iso-HPMP-Hx) is a very weak inhibitor of human HGPRT but remains a good inhibitor of both the parasite enzymes with K values of 2 μM and 5 μM for PfHGXPRT and PvHGPRT, respectively. The addition of pyrophosphate to the assay decreased the K values for the parasite enzymes by sixfold. This suggests that the covalent attachment of a second group to the ANPs mimicking pyrophosphate and occupying its binding pocket could increase the affinity for these enzymes

Synthesis of branched 9-[2-(2-phosphonoethoxy)ethyl]purines as a new class of acyclic nucleoside phosphonates which inhibit Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

The malarial parasite Plasmodium falciparum (Pf) lacks the de novo pathway and relies on the salvage enzyme, hypoxanthine–guanine–xanthine phosphoribosyltransferase (HGXPRT), for the synthesis of the 6-oxopurine nucleoside monophosphates. Specific acyclic nucleoside phosphonates (ANPs) inhibit PfHGXPRT and possess anti-plasmodial activity. Two series of novel branched ANPs derived from 9-[2-(2-phosphonoethoxy)ethyl]purines were synthesized to investigate their inhibition of PfHGXPRT and human HGPRT. The best inhibitor of PfHGXPRT has a Ki of 1 μM. The data showed that both the position and nature of the hydrophobic substituent change the potency and selectivity of the ANPs

Metal Ion-Binding Properties of 9-[(2-Phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an Isomer of the Antiviral Nucleotide Analogue 9-[(2-Phosphonometh¬oxy)ethyl]adenine (PMEA) : Steric Guiding of Metal Ion-Coordination by the Purine-Amino Group

The acidity constants of 3-fold protonated 9-[(2-phosphonomethoxy)ethyl]-2-aminopurine, H3(PME2AP)+, and the stability constants of the M(H;PME2AP)+ and M(PME2AP) complexes with M2+ = Ca2+, Mg2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+ or Cd2+ have been determined by potentiometric pH titrations in aqueous solution (25 °C; I = 0.1 M, NaNO3). It is concluded that in the M(H;PME2AP)+ species, the proton is at the phosphonate group and the metal ion at N7 of the purine residue. This “open” form allows macrochelate formation of M2+ with the monoprotonated phosphonate residue. The formation degree of this macrochelate amounts on average to 64 ± 13% (3σ) for those metal ions for which an evaluation was possible (Mn2+, Co2+, Ni2+, Cu2+, Zn2+). The identity of this formation degree indicates that the M2+/P(O)2−(OH) interaction occurs in an outersphere manner. The application of previously determined straight-line plots of log KMM(R-PO3)versus pKHH(R-PO3) for simple phosph(on)ate ligands, R-PO32−, where R represents a residue that does not affect metal ion binding, proves that all the M(PME2AP) complexes have larger stabilities than is expected for a sole phosphonate coordination of M2+. Combination with previous results allows the following conclusions: (i) The increased stability of the M(PME2AP) complexes of Ca2+, Mg2+ and Mn2+ is due to the formation of 5-membered chelates involving the ether-oxygen atom of the –CH2–O–CH2–PO32− residue; the formation degrees of these M(PME2AP)cl/O chelates for the mentioned metal ions vary between about 25% (Ca2+) to 40% (Mn2+). (ii) For the M(PME2AP) complexes of Co2+, Ni2+, Cu2+, Zn2+ or Cd2+ next to the mentioned 5-membered chelates a further isomer is formed, namely a macrochelate involving N7, M(PME2AP)cl/N7. The formation degrees of these macrochelates vary between about 30% (Cd2+) and 85% (Ni2+). (iii) The most remarkable observation of this study is that the shift of the NH2 group from C6 to C2 facilitates very significantly macrochelate formation of a PO32−-coordinated M2+ with N7 due to the removal of steric hindrance in the M(PME2AP) complexes. However, any M2+ interaction with N3 is completely suppressed, thus leading to significantly different coordination patterns than those observed previously with the antivirally active PMEA2− species