SOLVENT-DEPENDENT METAL-ION ADENINE RECOGNITION - QUANTIFICATION OF THE INTRAMOLECULAR EQUILIBRIA BETWEEN VARIOUS ISOMERS OF THE CU2+ COMPLEXES FORMED IN WATER-DIOXANE MIXTURES WITH THE ANIONS OF THE ANTIVIRAL 9-(2-(PHOSPHONOMETHOXY)ETHYL)ADENINE (PMEA), AN ADENOSINE-MONOPHOSPHATE (AMP) ANALOG

The stability constants of the 1:1 complexes formed between Cu2+ and 9-(2-(phosphonomethoxy)ethyl)adenine (PMEA2-), (phosphonomethoxy)ethane (PME2-), ethylphosphonate (EtP2-), or methylphosphonate (MeP2-) were determined by potentiometric pH titration in water and in water containing 30 or 50% (v/v) 1,4-dioxane (I = 0.1 M, NaNO3; 25-degrees-C). It is shown that the data for MeP2- and EtP2- fit on the same log K(Cu(R-PO3))Cu versus pK(H(R-PO3))H straight-line plots previously obtained for simple phosphate monoesters. With these reference lines it could be demonstrated in all solvents that the Cu(PME) complex has a higher stability than expected for a sole phosphonate-Cu2+ coordination, and this is attributed to the formation of five-membered chelates involving the ether oxygen present in the -OCH2PO32- residue. For Cu(PMEA) an additional stability increase is observed which has to be attributed to a metal ion adenine interaction, giving thus rise to equilibria between three different isomers. These equilibria were analyzed for the aqueous solution and the mixtures of water containing 30 or 50% 1,4-dioxane, and it is calculated that 17 (+/-3), 30 (+/-4), and 18 (+/-3)% of Cu(PMEA) exist as an isomer with a sole Cu2+- phosphonate coordination, 34 (+/-10), 44 (+/-9), and 28 (+/-9)% form the mentioned rive-membered chelate involving the ether oxygen and the remaining 49 (+/-10), 26 (+/-10), and 54 (+/-9)% are due to an isomer containing also a Cu2+-adenine interaction, Cu(PMEA)cl/Ad, respectively. Interestingly the formation degree of Cu(PMEA)cl/Ad passes through a minimum; i.e., small amounts of dioxane inhibit the Cu-adenine interaction-probably with N-3-while larger amounts favor it again. This result parallels a previous observation made with the macrochelate of Cu(5'-AMP) in which the metal ion is bound to the phosphate group and N-7 of the adenine residue. Similar structural alterations have to be expected for other metal ions, e.g., Zn2+. These observations indicate that small alterations of the polarity and water activity in an active-site cavity of an enzyme can considerably alter the structures of substrate complexes.