Novel ametantrone-amsacrine related hybrids as topoisomerase IIß poisons and cytotoxic agents.

The precise definition of the structural requirements for effective topoisomerase II poisoning by drug molecules is still an elusive issue. In the attempt to better define a pharmacophoric pattern, we prepared several conjugates combining the chemical features of two well-known topoisomerase II poisons, amsacrine and ametantrone. Indeed, an appropriate fusion geometry, which entails the anthracenedione moiety of ametantrone appropriately connected to the methanesulfonamidoaniline side chain of amsacrine, elicits DNA-intercalating properties, the capacity to inhibit the human topoisomerase IIß isoform, and cytotoxic activity resembling that of the parent compounds. In addition, the properties of the lateral groups linked to the anthracenedione group play an important role in modulating DNA binding and cell cytotoxicity. Among the compounds tested, 10, 11, and 19 appear to be promising for further development.

8-Hydroxynaphthalene-1,4-dione derivative as novel compound for glioma treatment.

Malignant gliomas continue to demand the search for improved chemotherapeutic solutions. In this work the results of a preliminary in vitro screening performed on a small library of compounds are disclosed. As a result 2-(2,4-dihydroxyphenyl)-8-hydroxy-1,4-naphthoquinone emerged as a promising therapeutic lead.

Cyclic carbonate synthesis catalysed by bimetallic aluminium-salen complexes.

The development of bimetallic aluminium-salen complexes [{Al(salen)}(2)O] as catalysts for the synthesis of cyclic carbonates (including the commercially important ethylene and propylene carbonates) from a wide range of terminal epoxides in the presence of tetrabutylammonium bromide as a cocatalyst is reported. The bimetallic structure of one complex was confirmed by X-ray crystallography. The bimetallic complexes displayed exceptionally high catalytic activity and in the presence of tetrabutylammonium bromide could catalyse cyclic carbonate synthesis at atmospheric pressure and room temperature. Catalyst-reuse experiments demonstrated that one bimetallic complex was stable for over 60 reactions, though the tetrabutylammonium bromide decomposed in situ by a retro-Menschutkin reaction to form tributylamine and had to be regularly replaced. The mild reaction conditions allowed a full analysis of the reaction kinetics to be carried out and this showed that the reaction was first order in aluminium complex concentration, first order in epoxide concentration, first order in carbon dioxide concentration (except when used in excess) and unexpectedly second order in tetrabutylammonium bromide concentration. Further kinetic experiments demonstrated that the tributylamine formed in situ was involved in the catalysis and that addition of butyl bromide to reconvert the tributylamine into tetrabutylammonium bromide resulted in inhibition of the reaction. The reaction kinetics also indicated that no kinetic resolution of racemic epoxides was possible with this class of catalysts, even when the catalyst was derived from a chiral salen ligand. However, it was shown that if enantiomerically pure styrene oxide was used as substrate, then enantiomerically pure styrene carbonate was formed. On the basis of the kinetic and other experimental data, a catalytic cycle that explains why the bimetallic complexes display such high catalytic activity has been developed.

Mechanism of cyclic carbonate synthesis from epoxides and CO2.

Three interconnected catalytic cycles account for the title reaction catalyzed by a bimetallic aluminum(salen) complex and Bu(4)NBr. In the first, Bu(4)NBr acts as a nucleophile to activate the epoxide. In the second, Bu(3)N generated in situ serves to activate CO(2). In the third, the aluminum(salen) complex brings the two activated species together so that the key bonds can be formed intramolecularly.

New naphthoquinone derivatives against glioma cells.

This work was aimed to the development of a set of new naphtoquinone derivatives that can act against glioma. The compounds were tested in order to find out their ability to inhibit the growth of glioma cells, and the results of these assays were correlated with electrochemical analysis and NMR-based reoxidation kinetic studies, suggesting that a redox mechanism underlies and may explain the observed biological behavior. In addition to a full description of the synthetic pathways, electrochemistry, NMR and single crystal X-ray diffraction data are provided.

Survival rate in patients affected by dementia followed by memory clinics (UVA) in Italy.

People affected by dementia experienced decreased life expectancy with a 2-4 times higher risk of death at a given age compared to non-demented people. Dementia represents a major cost to health care and society in the Western world and, particularly in Italy, is projected to become a high-resource demanding chronic disease. The present study aimed to estimate the average survival rate of a group of community dwelling elderly affected by dementia in Italy, and to assess the predictive variables associated with survival length. This retrospective study collected the data of patients (n = 290) who died from 2008 to 2012. The data were extracted from a cohort of over 2,000 patients from three outpatient Dementia Clinics of Genoa (Italy). Demographic data and other clinical parameters listed in the patients' clinical records were collected. The mean survival rate after dementia diagnosis was 3.3 ± 0.1 years, lower compared to the age-matched healthy population. The survival rate of these patients showed a significant correlation with age (n = 290; r = -0.16: p < 0.006), with the cognitive status (n = 285; r = 0.16: p < 0.007), with education (n = 204; r = 0.23: p < 0.001), with comorbidity (n = 138; r = -0.41: p < 0.0001), with depressive mood (n = 74; r = 0.44: p < 0.0001), and with the functional status (ADL: n = 242, r = 0.29: p < 0.0001; IADL: n = 243; r = 0.25: p < 0.0001). Multivariate regression revealed age, gender, and functional status as the main determinants informing patient survival. The study provides interesting and reliable data on the pivotal value of early dementia diagnosis in predicting longer survival and addresses comprehensive geriatric assessment, which encompasses most of the predictive variables provided by the study, as a remarkable tool in estimating life expectancy of patients with dementia.

Ellagic acid and polyhydroxylated urolithins are potent catalytic inhibitors of human topoisomerase II: an in vitro study.

Ellagic acid (EA), a natural polyphenol abundant in fruits and common in our diet, is under intense investigation for its chemopreventive activity resulting from multiple effects. EA inhibits topoisomerase II, but the effects on the human enzyme of urolithins, its monolactone metabolites, are not known. Therefore, the action of several synthetic urolithins toward topoisomerases II was evaluated, showing that polyhydroxylated urolithins, EA, and EA-related compounds are potent inhibitors of the α and ß isoforms of human topoisomerase II at submicromolar concentrations. Competition tests demonstrate a dose-dependent relationship between ATP and the inhibition of the enzyme. Docking experiments show that the active compounds bind the ATP pocket of the human enzyme, thus supporting the hypothesis that EA and polyhydroxylated urolithins act as ATP-competitive inhibitors of human topoisomerase II.

Urolithin as a converging scaffold linking ellagic acid and coumarin analogues: design of potent protein kinase CK2 inhibitors.

Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (K(i)=20 nM) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC, K(i)=60 nM). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X-ray structure-driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithin A as the bridging moiety led to the identification of 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one as a novel, potent and selective CK2 inhibitor, which shows a K(i) value of 7 nM against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments.