CNR ExploRA

Articolo in rivista, 2021, ENG, 10.3390/ijms22116028

Spectroscopic and in silico studies on the interaction of substituted pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one derivatives with c-myc g4-dna

Mulliri S.; Laaksonen A.; Spanu P.; Farris R.; Farci M.; Mingoia F.; Roviello G.N.; Mocci F.

Department of Chemical and Geological Sciences, University of Cagliari, Monserrato, I-09042, Department of Chemical and Geological Sciences, University of Cagliari, I-09042, Monserrato, Italy;, , Italy; State Key Laboratory of Materials-Oriented and Chemical Engineering, Nanjing Tech University, Nanjing, 210009, State Key Laboratory of Materials-Oriented and Chemical Engineering, Nanjing Tech University, Nanjing, 210009, China, , China; Division of Physical Chemistry, Department of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, 10691, Division of Physical Chemistry, Department of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, 10691, Stockholm, Sweden, , , Sweden; Division of Physical Chemistry, Department of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, 10691, Division of Physical Chemistry, Department of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, 10691, Stockholm, Sweden, , , Sweden; Centre of Advanced Research in Bionanoconjugates and Biopolymers, Petru Poni Institute of Macromolecular Chemistry, Iasi, 700487, Centre of Advanced Research in Bionanoconjugates and Biopolymers, Petru Poni Institute of Macromolecular Chemistry, 700487, Iasi, Romania, , Romania; Department of Engineering Sciences and Mathematics, Division of Energy Science, Luleå University of Technology, Luleå, SE-97187, Department of Engineering Sciences and Mathematics, Division of Energy Science, Luleå University of Technology, SE-97187, Luleå, Sweden, , Sweden; Istituto di Chimica Biomolecolare, ICB-CNR-Trav, La Crucca 3, Sassari, 07100, Istituto di Chimica Biomolecolare, ICB-CNR-Trav., La Crucca 3, 07100, Sassari, Italy;, , Italy; Istituto per lo Studio dei Materiali Nanostrutturati ISMN-CNR, Via U. La Malfa 153, Palermo, I-90146, Istituto per lo Studio dei Materiali Nanostrutturati ISMN-CNR, Via U. La Malfa 153, I-90146, Palermo, Italy;, , Italy; Istituto di Biostrutture e Bioimmagini, IBB-CNR, Via Mezzocannone 16, Naples, I-80134, Istituto di Biostrutture e Bioimmagini, IBB-CNR, Via Mezzocannone 16, I-80134, Naples, Italy, , , Italy; Istituto di Biostrutture e Bioimmagini, IBB-CNR, Via Mezzocannone 16, Naples, I-80134, Istituto di Biostrutture e Bioimmagini, IBB-CNR, Via Mezzocannone 16, I-80134, Naples, Italy, , , Italy

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2-4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (Tms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the Tms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery.

International journal of molecular sciences (Print) 22