Selective Binding and Redox-Activity on Parallel G-Quadruplexes by Pegylated Naphthalene Diimide-Copper Complexes

G-quadruplexes (G4s) are higher-order supramolecular structures, biologically important in the regulation of many key processes. Among all, the recent discoveries relating to RNA-G4s, including their potential involvement as antiviral targets against COVID-19, have triggered the ever-increasing need to develop selective molecules able to interact with parallel G4s. Naphthalene diimides (NDIs) are widely exploited as G4 ligands, being able to induce and strongly stabilize these structures. Sometimes, a reversible NDI-G4 interaction is also associated with an irreversible one, due to the cleavage and/or modification of G4s by functional-NDIs. This is the case of NDI-Cu-DETA, a copper(II) complex able to cleave G4s in the closest proximity to the target binding site. Herein, we present two original Cu(II)-NDI complexes, inspired by NDI-Cu-DETA, differently functionalized with 2-(2-aminoethoxy)ethanol side-chains, to selectively drive redox-catalyzed activity towards parallel G4s. The selective interaction toward parallel G4 topology, controlled by the presence of 2-(2-aminoethoxy)ethanol side chains, was already firmly demonstrated by us using core-extended NDIs. In the present study, the presence of protonable moieties and the copper(II) cavity, increases the binding affinity and specificity of these two NDIs for a telomeric RNA-G4. Once defined the copper coordination relationship and binding constants by competition titrations, ability in G4 stabilization, and ROS-induced cleavage were analyzed. The propensity in the stabilization of parallel topology was highlighted for both of the new compounds HP2Cu and PE2Cu. The results obtained are particularly promising, paving the way for the development of new selective functional ligands for binding and destructuring parallel G4s.

Physicochemical and Biopharmaceutical Evaluation of Casiopeina III-Ea, a New Compound with Antineoplastic Activity

In the present work, the physicochemical (pka, intrinsic solubility, Log D distribution coefficient) and biopharmaceutical characterization (IC50 studies in MDCK cells) of Casiopeina III-Ea, a Cu (II) mixed chelate compound, was carried out. These parameters will tell us about the behaviour of Casiopeina III-Ea, as a new antineoplastic agent, in physiological media. This basic research of the Faculty of Chemistry of the UNAM, is directed towards the maturation of a technology, which consists of the pharmaceutical development of an antineoplastic copper coordination compound Casiopeina III-Ea. Resumen. En el presente trabajo se realizó la caracterización fisicoquímica (pka, solubilidad intrínseca, coeficiente de distribución Log D) y biofarmacéutica (estudios IC50 en células MDCK) de Casiopeina III-Ea, un nuevo compuesto quelato mixto de cobre (II). Estos parámetros nos dirán mucho sobre el comportamiento de Casiopeina III-Ea, como un nuevo agente antineoplásico, en medios fisiológicos. Esta investigación básica de la Facultad de Química de la UNAM, está dirigida hacia la maduración de una tecnología, que consiste en el desarrollo farmacéutico de un compuesto de coordinación antineoplásico de cobre Casiopeina III-Ea.