Perspectives in the development of hybrid bifunctional antitumour agents

In spite of the development of a large number of novel target-specific antitumour agents, the single-agent therapy is in general not able to provide an effective durable control of the malignant process. The limited efficacy of the available agents (both conventional cytotoxic and novel target-specific) reflects not only the expression of defence mechanisms, but also the complexity of tumour cell alterations and the redundancy of survival pathways, thus resulting in tumour cell ability to survive under stress conditions. A well-established strategy to improve the efficacy of antitumour therapy is the rational design of drug combinations aimed at achieving synergistic effects and overcoming drug resistance. An alternative strategy could be the use of agents designed to inhibit simultaneously multiple cellular targets relevant to tumour growth/survival. Among these novel agents are hybrid bifunctional drugs, i.e. compounds resulting by conjugation of different drugs or containing the pharmocophores of different drugs. This strategy has been pursued using various conventional or target-specific agents (with DNA damaging agents and histone deacetylase inhibitors as the most exploited compounds). A critical overview of the most representative compounds is provided with emphasis on the HDAC inhibitor-based hybrid agents. In spite of some promising results, the actual pharmacological advantages of the hybrid agents remain to be defined. This commentary summarizes the recent advances in this field and highlights the pharmacological basis for a rational design of hybrid bifunctional agents

An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities

Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. In the last years, these natural compounds have been gaining an increasing attention from the scientific community for their wide range of biological activities, mainly due to their ability to interact with diverse enzymes and receptors in living organisms. In addition, coumarin nucleus has proved to be easily synthetized and decorated, giving the possibility of designing new coumarin-based compounds and investigating their potential in the treatment of various diseases. The versatility of coumarin scaffold finds applications not only in medicinal chemistry but also in the agrochemical field as well as in the cosmetic and fragrances industry. This review is intended to be a critical overview on coumarins, comprehensive of natural sources, metabolites, biological evaluations and synthetic approaches

New antimicrobials based on the adarotene scaffold with activity against multi-drug resistant staphylococcus aureus and vancomycin-resistant enterococcus

The global increase in infections by multi-drug resistant (MDR) pathogens is severely impacting our ability to successfully treat common infections. Herein, we report the antibacterial activity against S. aureus and E. faecalis (including some MDR strains) of a panel of adarotene-related synthetic retinoids. In many cases, these compounds showed, together with favorable MICs, a detectable bactericidal effect. We found that the pattern of substitution on adarotene could be modulated to obtain selectivity for antibacterial over the known anticancer activity of these compounds. NMR experiments allowed us to define the interaction between adarotene and a model of microorganism membrane. Biological assessment confirmed that the scaffold of adarotene is promising for further developments of non-toxic antimicrobials active on MDR strains

Use of antifuse-FPGAs in the Track-Sorter-Master of the CMS Drift Tube Chambers

The front-end system of the Silicon Drift Detectors (SDDs) of the ALICE experiment is made of two ASICs. The first chip performs the preamplification, temporary analogue storage and analogue-to-digital conversion of the detector signals. The second chip is a digital buffer that allows for a significant reduction of the connection from the front-end module to the outside world. In this paper, the results achieved on the first complete prototype of the front-end system for the SDDs of ALICE are presented

DT Sector Collector electronics design and construction

The CMS detector at LHC is equipped with Drift Tubes (DT) chambers for muon detection and triggering in the barrel region. The Sector Collector (SC) modules collect the track segments reconstructed by on-chamber trigger electronics. Data from different chambers are aligned in time and sent to the subsequent reconstruction processors via optical links. Several FPGA devices performing the processing of the data were designed in VHDL, including spy features to monitor the trigger data flow. A test jig was set up with custom hardware and software in order to fully validate final production boards. Installation and commissioning in CMS provided first experience with the synchronization and monitoring tools

Event Generators for Bhabha Scattering

The results obtained by the "Event Generators for Bhabha Scattering" working group during the CERN Workshop "Physics at LEP2" (1994/1995) are presented.Comment: 70 pages, PostScript file. To appear in the Report of the Workshop on Physics at LEP2, G. Altarelli T. Sjostrand and F. Zwirner ed

Design and Test of the Off-Detector Electronics for the CMS Barrel Muon Trigger

Drift Tubes chambers are used in the CMS barrel for tagging the passage of high Pt muons generated in a LHC event and for triggering the CMS data read out. The Sector Collector (SC) system synchronizes the track segments built by trigger modules on the chambers and deliver them to reconstruction processors (Track Finder, TF) that assemble full muon tracks. Then, the Muon Sorter (MS) has to select the best four candidates in the barrel and to filter fake muons generated by the TF system redundancy. The hardware implementations of the Sector Collector and Muon Sorter systems satisfy radiation, I/O and fast timing constraints using several FPGA technologies. The hardware was tested with custom facilities, integrated with other trigger subsystems, and operated in a beam test. A test beam on a 40 MHz bunched beam validated the local trigger electronics and off-detector prototype cards and the synchronization tools. The CMS Magnet Test and Cosmic challenge in 2006 proved stable and reliable operation of the Drift Tubes trigger and its integration with other trigger systems and with the readout system. Constraints, design, test and operation of the modules are presented

Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors

Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability