Synthesis and cytotoxic activity of 3-[2-(1H-Indol-3-yl)-1,3-thiazol-4-yl]-1H-pyrrolo[3,2-c]pyridine hydrobromides, analogues of the marine alkaloid nortopsentin

A new series of thiazole nortopsentin analogues with a 5-azaindole moiety was conveniently synthesized in good to excellent yields by an Hantzsch reaction between thioamides and \u3b1-bromoacetyl compounds. The cytotoxic activity of the new derivatives was tested against different human tumor cell lines of the NCI full panel. All tested compounds were active against all of the investigated cell lines showing GI50 values from micro to submicromolar levels. Some of the new analogues exhibited good selectivities against different NCI sub-panels

Recent Developments in the Inhibition of Bacterial Adhesion as Promising Anti-Virulence Strategy

Infectious diseases caused by antimicrobial-resistant strains have become a serious threat to global health, with a high social and economic impact. Multi-resistant bacteria exhibit various mechanisms at both the cellular and microbial community levels. Among the different strategies proposed to fight antibiotic resistance, we reckon that the inhibition of bacterial adhesion to host surfaces represents one of the most valid approaches, since it hampers bacterial virulence without affecting cell viability. Many different structures and biomolecules involved in the adhesion of Gram-positive and Gram-negative pathogens can be considered valuable targets for the development of promising tools to enrich our arsenal against pathogens

Rapid prototyping for enhanced dynamic positioning systems

The paper aims to show the design procedure for a Class-2 dynamic positioning system, from initial conceptualisation to factory assessment test. The approach involves the use of simulation-based design combined with hardware in the loop testing. This kind of approach involves a detailed knowledge of the investigated ship but gives significant well-known advantages. The main are: the reduction of the design duration, the optimisation of the system performance, the debug of the control logics before the installation onboard, the reduction of the sea trial costs. Finally, the result of this process is a product ready to be installed onboard. Moreover, over the years, the interest of the classification societies in simulation results for certifying such systems is increased. This study shows both the approach and the results of designing a dynamic positioning system for a Platform Supply Vessel. A custom simulation platform has been developed to have realistic feedbacks of the case-study ship. The DP controller structure, including regulator, force and thrust allocation; have been conceptualised, and then, after the porting procedure, the DP software has been downloaded in the real PCL. Several HIL tests have been carried out to fine-tune the controller parameters. The results show, under different environmental conditions, the respect of the design criteria

A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged as promising pharmacological targets for the treatment of several solid and hematological tumors. Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been correlated to the aggressive nature of these tumors because of its key role in cell cycle progression and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes of chemoresistance, representing a promising pharmacological target. In this study, we report the synthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth of PATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6b was the most active compound, with IC50 values ranging from 5.7 to 10.7 M. Molecular docking of 6b into the active site of CDK1 showed the ability of the compound to interact effectively with the adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis (which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1 expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction, showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxic activity, induces apoptosis, and targets CDK1, supporting further studies for the development of similar compounds against PDAC

1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1

A new series of nortopsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,3,4-oxadiazole or 1,3,4-thiadiazole moiety, was efficiently synthesized. The antiproliferative activity of all synthesized derivatives was evaluated against five pancreatic ductal adenocarcinoma (PDAC) cell lines, a primary culture and a gemcitabine-resistant variant. The five more potent compounds elicited EC50 values in the submicromolar-micromolar range, associated with a significant reduction in cell migration. Moreover, flow cytometric analysis after propidium iodide staining revealed an increase in the G2-M and a decrease in G1-phase, indicating cell cycle arrest, while a specific ELISA demonstrated the inhibition of CDK1 activity, a crucial regulator of cell cycle progression and cancer cell proliferation

A peculiar Spanish Timber Floor, the "Revoltón": a Diagnostic Example at the "Palacio del Marqués de Benicarló"

The paper deals with the application of the Italian method for assessing on-site and diagnosing timber elements to a distinctive Spanish type of horizontal structure called "revolton" i.e. jack arch floor. As in Spain does not exist a specific regulation for the on-site diagnosis of timber elements, this analysis was performed according to the Italian standard UNI 11119. Due to the peculiar features of the jack arch floor some modifications were applied to the method. During spring 2012 the authors had the opportunity to carry out a pilot project by making a diagnostic analysis on a whole three stories building. The building, Marquees of Benicarlo's Palace, located in Spain in the town of Benicarlo, between Barcelona and Valencia, was erected during the second half of the XVIII century. It maintains the original internal distribution and structure, and it is characterized by precious ceramic decorations on walls and floors. All the horizontal structures studied inside the palace were jack arch floor except the roof structure that was also made of timber. The results of the project described in the paper clarify the specific problems of the horizontal structures and the roof surveyed during the fieldwork. These results are accompanied by several plans that represent the information recovered on-site and lead to a complete assessment of the structures. The plans include the grading based on wood defects, the local moisture content of wood, the superficial and inner decay due to insects and rot and the deformation of the joists. In this way it was possible to locate the areas of the palace where more problems were concentrated, and better understand the causes and origin of the damages.Diodato, M.; Macchioni, N.; Brunetti, M.; Pizzo, B.; Nocetti, M.; Burato, P.; Sozzi, L.... (2013). A peculiar Spanish Timber Floor, the "Revoltón": a Diagnostic Example at the "Palacio del Marqués de Benicarló". Advanced Materials Research. 778:1064-1071. doi:10.4028/www.scientific.net/AMR.778.1064S10641071778E. Cubero, El lujo señorial de lo sencillo (The noble luxury of simplicity), Revistart: Revista de las artes, 125 (2007) pp.8-10.C. Colón de Carvajal y Fibla, La casa-palacio de los Marqueses de Benicarló (The Marquees of Benicarló's Palace), Numen. Revista de excelencia, (2011) on-line.La casa de los Marqueses de Benicarló nos abre sus puertas (The Marquees of Benicarló's House opens its doors), MasQrural, 21 (2008) pp.85-94.M. Diodato, Variaciones constructivas y formales en forjados y cubiertas (Constructive and formal variations in floors and roofs), in: F. Vegas, C. Mileto, Valencia. Centro histórico. Ocho siglos de arquitectura residencial (Historic centre. Eight Centuries of residential architecture), Generalitat Valenciana, Valencia, (2013).N. Macchioni, Inspection techniques for ancient wooden structures, in: P. Roca, J.L. Gonzalez, E. Onate, P.B. Lourenco (Eds. ), Structural analysis of historical constructions II: possibilities of numerical and experimental techniques, CIMNE, Barcelona, 1998, pp.149-162.N. Macchioni, M. Piazza, Italian standardization activity in the field of diagnosis and restoration of ancient timber structures, in: F.M. Mazzolani (Ed. ), Protection of historical buildings - PROHITECH 09, vol. 1-2, Taylor & Francis Group, London, 2009, pp.349-353.G. Lear, B. Kasal, R. Anthony, Resistance drilling, in: B. Kasal, T. Tannert (Eds. ), In situ assessment of structural timber, State of the art report of the RILEM TC 215-AST, Springer.N. Macchioni, M. Brunetti, B. Pizzo, P. Burato, M. Nocetti, S. Palanti, The timber structures in the Church of the Nativity in Bethlehem: Typologies and diagnosis, Journal of cultural heritage, Vol. 13 Issue 4 Supplement S (2012) pp. E42-E53

Understanding Spanish Timber Jack Arch Floors: Examples of Assessment and Conservation Issues

[EN] Jack arch floors are structures made of timber joists, with round or squared section, and segmental vaults either made of flat tiles or poured plaster conglomerate. They are especially diffused along the Mediterranean coast of Spain and can be considered as a main feature of the historical and vernacular architecture of the area. In order to assess and grade these structures several Spanish standards have been considered; however, even if the information contained is useful the Italian standard for the on-site diagnosis UNI 11119 of 2004 has been preferred. The method described in this standard leads the assessment through the grading of each and every timber element and the assignation of bearing properties that are essential for the consolidation project. This article will expose three examples of jack arch floors of the Valencian Community graded using the Italian standard and the conservation issues that arise from the results.Diodato, M.; Macchioni, N.; Brunetti, M.; Pizzo, B.; Nocetti, M.; Burato, P.; Sozzi, L.... (2015). Understanding Spanish Timber Jack Arch Floors: Examples of Assessment and Conservation Issues. International Journal of Architectural Heritage. 9(6):641-654. https://doi.org/10.1080/15583058.2015.104119364165496Diodato, M., Macchioni, N., Brunetti, M., Pizzo, B., Nocetti, M., Burato, P., … Mileto, C. (2013). A Peculiar Spanish Timber Floor, the «Revoltón»: A Diagnostic Example at the «Palacio del Marqués de Benicarló». Advanced Materials Research, 778, 1064-1071. doi:10.4028/www.scientific.net/amr.778.1064Lear, G., Kasal, B., & Anthony, R. (2010). Resistance Drilling. RILEM State of the Art Reports, 51-57. doi:10.1007/978-94-007-0560-9_5Macchioni, N., Brunetti, M., Pizzo, B., Burato, P., Nocetti, M., & Palanti, S. (2012). The timber structures in the Church of the Nativity in Bethlehem: Typologies and diagnosis. Journal of Cultural Heritage, 13(4), e42-e53. doi:10.1016/j.culher.2012.10.004Riggio, M., Anthony, R. W., Augelli, F., Kasal, B., Lechner, T., Muller, W., & Tannert, T. (2013). In situ assessment of structural timber using non-destructive techniques. Materials and Structures, 47(5), 749-766. doi:10.1617/s11527-013-0093-6Tannert, T., Anthony, R. W., Kasal, B., Kloiber, M., Piazza, M., Riggio, M., … Yamaguchi, N. (2013). In situ assessment of structural timber using semi-destructive techniques. Materials and Structures, 47(5), 767-785. doi:10.1617/s11527-013-0094-5Vegas, F. (2013). Parameterisation of Gypsum Mortar for Alternative Structural Consolidation of Traditional Floors. Advances in Materials, 2(4), 48. doi:10.11648/j.am.20130204.1

Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma

Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas

Structural Manipulations of Marine Natural Products Inspire a New Library of 3-Amino-1,2,4-Triazine PDK Inhibitors Endowed with Antitumor Activity in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the main aggressive types of cancer, characterized by late prognosis and drug resistance. Among the main factors sustaining PDAC progression, the alteration of cell metabolism has emerged to have a key role in PDAC cell proliferation, invasion, and resistance to standard chemotherapeutic agents. Taking into account all these factors and the urgency in evaluating novel options to treat PDAC, in the present work we reported the synthesis of a new series of indolyl-7-azaindolyl triazine compounds inspired by marine bis-indolyl alkaloids. We first assessed the ability of the new triazine compounds to inhibit the enzymatic activity of pyruvate dehydrogenase kinases (PDKs). The results showed that most of derivatives totally inhibit PDK1 and PDK4. Molecular docking analysis was executed to predict the possible binding mode of these derivatives using ligand-based homology modeling technique. Evaluation of the capability of new triazines to inhibit the cell growth in 2D and 3D KRAS-wild-type (BxPC-3) and KRAS-mutant (PSN-1) PDAC cell line, was carried out. The results showed the capacity of the new derivatives to reduce cell growth with a major selectivity against KRAS-mutant PDAC PSN-1 on both cell models. These data demonstrated that the new triazine derivatives target PDK1 enzymatic activity and exhibit cytotoxic effects on 2D and 3D PDAC cell models, thus encouraging further structure manipulation for analogs development against PDA