Molecular Recognition between Copper(II) Chelates with Polyamines and the Antiviral Drug Acyclovir

Abstract

During the last decades, the Research Group FQM-283 “Transition metal complexes with bioinorganic and/or therapeutic interest” has been devoted to the study of molecular recognition patterns between metal chelates and nucleobases or analogue ligands. In this context, we propose to move forward in the study of this phenomenon using synthetic nucleosides derived from purine bases. Appropriate structural revisions in the Cambridge Structural Database (CSD) base encourage to perform a comprehensive study on acyclovir (acv). Its interest is based on: a) acv is an antiviral drug with an extensive use, b) the chemical stability of the N9-acyclic substituent contained in its guanine moiety and c) the limited information available about its behaviour as ligand. From previous studies, it is well-known that the preferred donor atom of this synthetic nucleoside for metal binding is N7, which is suitable for binding intermediate to soft metal ions (according to Pearson criterion). Likewise, N7 is the preferred protonation site. The structure of acyclovir (anhydrous and hydrates) as well as the structure of acv organic adducts and salts with different organic and inorganic anions have been reported already. Regarding metal complexes, the observed metal binding patterns mainly consist in a coordination bond N7-metal, or the cooperation of this bond with an intra-molecular interligand interaction (O-H···O6 or N-H···O6), with the exception of two compounds where acv acts in the N7,O6-chelating mode or in the μ- N7,O(ol)-bridging mode. A preliminary study of our research group about copper(II) chelates with iminodiacetate (IDA) or glycilglycinate (glygly) and acv emphasized the relevance of the cooperation between the Cu-N7 bond and the (glygly)N-H···O6 interaction. On this basis, the idea of testing the potential of acv as ligand came out, expanding the metal biding abilities of acv and the capability of different copper(II)-polyamine chelates as acv receptors. While this research was being developed, fruitful discussions regarding outcoming results lead to new goals, applying the most basic scientific methodology. Results in this Ph.D. thesis include, among others, (a) some compounds without acv, (b) a variety of ternary copper(II)-chelating-acv complexes, (c) a tetranuclear molecular complex with nickel(II) containing coordinated anionic acv, which adopts a novel N7-O6-bridge mode, (d) a copper(II) polymer with monodentate acv and multifunctional acv (tetradentate, bridge and chelating) without precedent in the coordination of nucleosides to metals, and (e) a macrocyclic chelate of copper(II) with neutral acv and anionic acv, being both of them non-coordinated to the metal. This Ph.D. thesis include these and other results in four articles published in indexed JCR international journals, a draft manuscript due to be submitted to a prestigious indexed journal and a section that includes recent and novel results, which will be submitted for its publication in the near future.