Riccardo Bonsignore

Selective G-quadruplex stabilizers: Schiff-base metal complexes with anticancer activity

The affinity of three square-planar nickel(II) (1), copper(II) (2) and zinc(II) (3) Schiff-base complexes for wild-type human telomeric (h-Telo) and protooncogene c-myc G-quadruplex (G4) DNA was investigated by UV-visible absorption spectroscopy and circular dichroism. DNA-binding constants (Kb) were determined by spectrophotometric titrations for both G4-DNA and B-DNA. The results obtained point out that the three metal complexes selectively bind G4-DNA with higher affinity, up to two orders of magnitude, with respect to B-DNA. The nickel(II) complex 1 was found to be the most effective G4-DNA stabilizer and the Kb values decrease in the order 1 > 2 ≈ 3. Innovative computational investigations, consisting of molecular dynamics (MD) simulations followed by density functional theory/molecular mechanics (DFT/MM) calculations, provide atomistic support for the interpretation of the binding mechanism to G4-DNA by end stacking and also of the experimental affinity order. Interestingly, 1 is able to induce G4-DNA formation of h-Telo sequences, also in the absence of K+ cations. This last result is nicely confirmed and highlighted by polymerase chain reaction (PCR) stop assays, which show the ability of the title compounds to induce and stabilize G4 structures inhibiting the amplification of PCR products. Finally, compounds 1–3 showed concentration and time-dependent cytotoxicity towards HeLa and MCF-7 human cancer cell lines, inducing significant effects on cell cycle distribution with G2/M arrest in HeLa cells and G0/G1 arrest in MCF-7 cells. Overall, the PCR inhibition and anticancer activity of the three compounds decreases in the same order 1 > 2 ≈ 3, in excellent correlation with the G4-DNA-binding affinity, implying that G4-DNA is the biotarget for their biological activity.

Heterocyclic Scaffolds for the Treatment of Alzheimer's Disease

BACKGROUND The treatment and diagnosis of Alzheimers Disease (AD) are two of the most urgent goals for research around the world. The cognitive decline is generally associated with the elevated levels of extracellular senile plaques, intracellular neurofibrillary tangles (NFTs), and with a progressive shutdown of the cholinergic basal forebrain neurons transmission. Even if several key targets are under fervent investigation in the cure of AD, till now, the only approved therapeutic strategy is the treatment of symptoms by using cholinesterases inhibitors. It has been demonstrated that both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes are not only responsible of acetylcholine levels, but also play an pivotal role in Aβ-aggregation during the early stages of senile plaque formation. On the other hand the difficult management of AD is also related to effective diagnostic methods and efficient assays for the study of pathological features. In such complex a wide framework, heterocyclic molecules are essential backbone to build new and selective drugs as well as diagnostic probes. METHODS The goal of this review is to examine a selected sample of relevant applications of five- and six-membered heterocycles in ADs therapeutic approaches. RESULTS Concerning the research on AD, the contribution of heterocyclic compounds is huge and here we report some representative examples. The review is organized in two main sections focused on five and six-membered heterocycles. The analyzed cases have been classified on the base of the structural features of molecules, taking into account the progressive increase in heteroatoms number. CONCLUSION The discovery of an effective therapy or a diagnostic protocol for AD is still far, but consistent improvements are underway and contribution of heterocyclic compounds will be consistent and hopefully determinant.

New benzothieno[3,2-d]-1,2,3-triazines with antiproliferative activity: synthesis, spectroscopic studies, and biological activity.

New benzothieno[3,2-d]-1,2,3-triazines, together with precursors triazenylbenzo[b]thiophenes, were designed, synthesized and screened as anticancer agents. The structural features of these compounds prompted us to investigate their DNA binding capability through UV-vis absorption titrations, circular dichroism, and viscometry, pointing out the occurrence of groove-binding. The derivative 3-(4-methoxy-phenyl)benzothieno[3,2-d]-1,2,3-triazin-4(3H)-one showed the highest antiproliferative effect against HeLa cells and was also tested in cell cycle perturbation experiments. The obtained results assessed for the first time the anticancer activity of benzothieno[3,2-d]-1,2,3-triazine nucleus, and we related it to its DNA-binding properties.

Does ligand symmetry play a role in the stabilization of DNA G-quadruplex host-guest complexes?

In efforts to find agents with improved biological activity against cancer cells, recent years have seen an increased interest in the study of small molecules able to bind the deoxyribonucleic acid (DNA) when it assumes secondary structures known as G-quadruplexes (G4s) preferring them over the B form. Currently, several compounds reported in literature have already shown to be good candidates as G4s DNA stabilizers. Even though some specific features for the G4s affinity are known, such as a π-delocalized system able to stack at the top/end of a G-tetrad and positively charged substituents able to interact with the grooves, it is not clear yet what kind of structural features affect more the G4 arrangement. This is mainly due to the structure heterogeneity of both the G4 stabilizer compounds and the DNA G4s isoforms. In this review, we aim to classify some known G4 binders by analyzing them from a new perspective surprisingly never approached up to date: the symmetry features. Molecular symmetry could be responsible for the specific binding mode to the G4-DNA but could also be crucial in determining different isoform affinity. We propose to classify the G4s stabilizers in five main point group symmetry classes. This classification could be useful to design new ligands able to stabilize a specific G-quadruplex isoform, in order to increase the selectivity of new potential anticancer G-quadruplex targeting drugs, a goal yet highly sought by researchers.

Kinase Inhibitors in Multitargeted Cancer Therapy

The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual singletarget drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of a multi-target approach, the closely related evolutionary members of the tyrosine kinase family are ideal candidates. Indeed, tyrosine kinase activities are not only critical in tumor phenotype maintenance, but also modulate several functions in the tumor microenvironment. Consequently, several multikinase inhibitors were approved in the last decade, and many new molecules are currently in preclinical or clinical development. In the present review we report on the most widely FDA-approved multitargeted drugs, discussing about their mechanism of action and outlining the clinical trials that have brought them to approval.

Metal Ions and Metal Complexes in Alzheimer’s Disease

BACKGROUND Alzheimers disease (AD) is the most common form of dementia that seriously affects daily life. Even if AD pathogenesis is still subject of debate, it is generally accepted that cerebral cortex plaques formed by aggregated amyloid-β (Aβ) peptides can be considered a characteristic pathological hallmark. It is well known that metal ions play an important role in the aggregation process of Aβ. METHODS This review focuses on the anti-Aβ aggregation activity of chelating ligands as well as on the use of metal complexes as diagnostic probes and as potential drugs. CONCLUSION While chelating agents, such as curcumin or flavonoid derivatives, are currently used to capture metal ions responsible for Aβ aggregation, the potential application of platinum, ruthenium and cobalt complexes, among others, of several heterocyclic ligands, represents a promising new strategy to fight AD.

Profiles and Sources of PAHs in Sediments from an Open-Pit Mining Area in the Peruvian Andes

The Peruvian Andes are one of the most productive areas for mining and therefore also one of the most exposed to these sources of pollution. This article reports the characterization of Polycyclic Aromatic Hydrocarbons (PAHs) in sediments of Cerro de Pasco area (Peru) located close to a large open-pit mine and, in recent years, several reports have provided evidence of environmental contamination and related health problems. Investigations were carried out into the fifteen PAHs identified by the US-Environment Protection Agency (US-EPA) as requiring priority monitoring, other non US-EPA listed PAHs and perylene were also investigated in order to obtain further information on their origins. By considering the results of all the analysis, the total PAHs concentration varies from 13–1009 μg/Kg with a mean value of 224 μg/Kg. The concentrations of PAHs found in all 12 stations were lower than the effect range low (ERL). PAHs, in the most of the samples, have origin from high temperature processes. Taking into consideration that perylene concentrations were low, a small quantity of polycyclic hydrocarbons may be originated from biological activity.