Allene-derived gold and platinum complexes: synthesis and first applications in catalysis

We report here the synthesis, full characterisation and first application in catalysis of novel Au(I), Au(III) and Pt(II) carbene-type complexes formed from bis(pyridyl)allenes. The catalytic activity of the new Au(I)-complexes in the cylisation of 1,6-enynes, benchmark reaction for new Au and Pt complexes, was comparable to Au(I)-state-of-the-art catalysts used in these reactions. Reactions with the new Au(III)- and Pt(II)-complexes ocurred under milder conditions than the reported with AuCl3 and PtCl2

Anticancer activity and DNA interaction of bis(pyridyl)allene-derived metal complexes

The constant need for novel drugs has prompted the scientific community to explore alternative structures to natural products and small and medium size organic compounds used in classic medicinal and pharmaceutical chemistry. Since the discovery of cisplatin, organometallic compounds have revealed great potential as metallodrugs and their development has exponentially grown in recent years. In this manuscript, we describe our efforts towards the synthesis of new metallodrugs by reaction of bis(pyridyl)allenes and metal complexes. Two classes of compounds are presented: one in which the allene structure is intact and the metal (Pd(II), Pt(IV) or Au(III)) coordinates to the pyridine-nitrogens; and another, in which one of the pyridines cyclises into a gold-activated allene to form β-N-stabilised gold carbenes. Both classes of compounds are active catalysts in important organic reactions, and are also promising antimicrobial, antifungal and anticancer agents. In this work, we describe the promising anticancer activity, against breast cancer cells, of the gold carbene complexes, and preliminary studies of their interaction with DNA, including non-canonical DNA structures. Our results have revealed an unusual selective stabilisation of hTeloC i-motif by one of the Au(III) carbene complexes, that opens up exciting opportunities for further development of novel DNA-binding metallodrugs

Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First InVivo{In Vivo} Experiments

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex $\textbf{Pt1}$ significantly reduces fungal load in an in vivoG. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases

Study of allene-based ligands for transition metal complexes – synthesis and applications in catalysis and as metallodrugs

From being regarded as a chemical curiosity the allene functional moiety emerged as one of very useful synthetic tools of modern organic chemistry over the past few decades. Inherent axial chirality of the allene skeleton makes it especially attractive in the context of highly demanded new asymmetric synthesis methods. This doctoral thesis explores the use of the allene group as a backbone in a new ligand scaffold for the synthesis of novel allene-derived transition metal complexes for applications in catalysis and as metallodrugs. Examples of optically active allene-containing complexes equipped mainly with phosphorus-based donor groups have been developed in the past decade and some of them have been found to act as catalysts in asymmetric transformations. However, the field remains highly underexplored. This doctoral study presents the development and synthesis of new allene-based ligand candidates as well as the use of reported examples in unprecedented settings. These ligands were used to prepare a range of novel symmetric, non-symmetric, neutral and cationic complexes with Pd, Pt and Au metal centres. Depending on the nature of the metal used, the allene-based ligands could retain their cumulene system in the new organometallic compounds. While in the presence of others, the cyclisation afforded new carbene-type complexes (Figure 1). The new series of organometallic compounds were extensively characterised including techniques such as HR-MS, X-ray diffraction, variable temperature NMR spectroscopy and cyclic voltammetry. The synthesis of allene-derived metal complexes was followed by the investigation of their catalytic activity and bioactivity. The new compounds performed well as catalysts in Heck reaction, cyclisation of 1,6-enynes or metal-catalysed nucleophilic addition to allenes. Preliminary testing of the antimicrobial properties of new complexes showed their high toxicity towards bacteria and fungi with one hit compound currently being evaluated in in vivo models. The antiproliferative properties against MDA-MB-231 human breast adenocarcinoma cancer cell line was probed, showing cytotoxicity in a low micromolar range for selected compounds. The new allene-derived complexes were also found to interact with non-canonical DNA secondary structures such as i-motif and G-quadruplex, giving a first look at potential mechanism of action of these metallodrug candidates. Preparation of optically enriched allene-based ligands for the asymmetric version of the project was also briefly explored

Improving the level of sustainable development in industry 4.0 context : a new approach

Purpose: Sustainable manufacturing models are currently being sought, the implications of which in manufacturing companies will be an integral part of their functioning in the Industry 4.0 (I4.0) concept. This paper aims to review the application of Multi-Criteria Decision-Making methods (MCDM) to assess the Sustainable Development (SD) level in industries and build a new approach to maintain and increase SD in a company. Design/Methodology/Approach: The research methodology is based on the detailed literature studies of SD in manufacturing, applying MCDM methods and the use of an Information Technology (IT) in the I4.0 within a manufacturing company. Findings: The overview of the related works allowed for the identification of the novel approach to SD assessment and measurement in manufacturing enterprises, which integrates the SD level assessment and an IT in the I4.0 and allows to determinate the essential SD objectives for evaluation and monitoring within an enterprise using the Fuzzy Technique for Order of Preference by Similarity to Ideal Solution (F-TOPSIS) method and Intuitionistic Fuzzy Weighted Averaging (IFWA) operator. Practical Implications: The functional significance of this work was determined in the form of a framework, the implementation of which will allow managers to assess and constantly monitor the implementation process of SD strategy. At the same time, the application of IT in I4.0 ensures the ability to control them. Originality/Value: As highlighted in the state-of-the-art analysis, none of the existing works supports all the presented features of the proposed approach to improving sustainable development in manufacturing in the Industry 4.0 context using F-TOPSIS and IFWA.peer-reviewe

Modeling the Effectiveness of Intelligent Systems in Public Transport That Uses Low-Carbon Energy: A Case Study

Cities have been struggling for many years with many transport problems, including the impact of carbon monoxide emitted by vehicles on the environment, traffic jams, high energy consumption, numerous accidents or high infrastructure costs. There is also a dynamic growth of vehicles on the roads, which is why an increasing number of cities are introducing intelligent transportation systems (ITS), which is part of the concept of smart cities. This paper proposes a new matrix to assess the effects of the ITS implementation in the context of a concept Smart City, which consists of five criteria: (1) movement speed; (2) safety; (3) environmental; (4) economic; (5) satisfaction and amenities for society/passengers. In this new approach the benchmark values of the indicators assigned to the criteria are involved and, therefore, it is possible to determine the level of effectiveness of the ITS in public transport that uses low-carbon energy. This research used literature studies to establish the criteria of effectiveness of ITS as well as a case study, namely public transport that uses low-carbon energy in a Polish city, which had the largest fleet of electric buses in Poland and implements and uses an ITS. Both, the theoretical and the empirical research results demonstrate the usefulness and potency of the proposed matrix to assess the effects of the ITS implementation in cities in the context of the development of a smart city. In that way, the proposed approach may be a useful tool for measuring the effects of ITS implementation in cities

Decision-Tree Based Methodology Aid in Assessing the Sustainable Development of a Manufacturing Company

Nowadays, achieving the objectives of sustainable development (SD) within a manufacturing company, through introducing and integrating sustainability into a development strategy, is a key parameter in gaining a competitive advantage in the market. The objective of this study was to develop a decision-tree based methodology to facilitate SD assessment in a manufacturing company, which consists of five main components: (1) Determination of SD indicators based on literature analysis, (2) Using the Analytic Hierarchy Process (AHP) method which determines the priority of the SD criteria, (3) Collecting data to determine the values of the key objectives SD, (4) Using a decision tree to build scenarios of possible actions to increase the level of SD, (5) Indicating recommended actions for continuous monitoring of progress towards reaching SD objectives. In the proposed approach, the use of the AHP method allowed for indicating the most important SD indicators, which made it possible to limit the number of queries to manufacturers on data from real companies regarding the values of SD indicators. Finally, the methodology was applied and verified within a real manufacturing company in order to assist the Management Board in making projections about future actions regarding an increase in SD level

Allene-derived gold and platinum complexes: synthesis and first applications in catalysis

We report here the synthesis, full characterisation and first application in catalysis of novel Au(I), Au(III) and Pt(II) carbene-type complexes formed from bis(pyridyl)allenes. The catalytic activity of the new Au(I)-complexes in the cylisation of 1,6-enynes, benchmark reaction for new Au and Pt complexes, was comparable to Au(I)-state-of-the-art catalysts used in these reactions. Reactions with the new Au(III)- and Pt(II)-complexes ocurred under milder conditions than the reported with AuCl3 and PtCl2

Effect of Capsaicin and Other Thermo-TRP Agonists on Thermoregulatory Processes in the American Cockroach

Capsaicin is known to activate heat receptor TRPV1 and induce changes in thermoregulatory processes of mammals. However, the mechanism by which capsaicin induces thermoregulatory responses in invertebrates is unknown. Insect thermoreceptors belong to the TRP receptors family, and are known to be activated not only by temperature, but also by other stimuli. In the following study, we evaluated the effects of different ligands that have been shown to activate (allyl isothiocyanate) or inhibit (camphor) heat receptors, as well as, activate (camphor) or inhibit (menthol and thymol) cold receptors in insects. Moreover, we decided to determine the effect of agonist (capsaicin) and antagonist (capsazepine) of mammalian heat receptor on the American cockroach’s thermoregulatory processes. We observed that capsaicin induced the decrease of the head temperature of immobilized cockroaches. Moreover, the examined ligands induced preference for colder environments, when insects were allowed to choose the ambient temperature. Camphor exposure resulted in a preference for warm environments, but the changes in body temperature were not observed. The results suggest that capsaicin acts on the heat receptor in cockroaches and that TRP receptors are involved in cockroaches’ thermosensation

Anticancer activity and DNA interaction of bis(pyridyl)allene-derived metal complexes

The constant need for novel drugs has prompted the scientific community to explore alternative structures to natural products and small and medium size organic compounds used in classic medicinal and pharmaceutical chemistry. Since the discovery of cisplatin, organometallic compounds have revealed great potential as metallodrugs and their development has exponentially grown in recent years. In this manuscript, we describe our efforts towards the synthesis of new metallodrugs by reaction of bis(pyridyl)allenes and metal complexes. Two classes of compounds are presented: one in which the allene structure is intact and the metal (Pd(II), Pt(IV) or Au(III)) coordinates to the pyridine-nitrogens; and another, in which one of the pyridines cyclises into a gold-activated allene to form b-N-stabilised gold carbenes. Both classes of compounds are active catalysts in important organic reactions, and are also promising antimicrobial, antifungal and anticancer agents. In this work, we describe the promising anticancer activity, against breast cancer cells, of the gold carbene complexes, and preliminary studies of their interaction with DNA, including non-canonical DNA structures. Our results have revealed an unusual selective stabilisation of hTeloC i-motif by one of the Au(III) carbene complexes, that opens up exciting opportunities for further development of novel DNA-binding metallodrugs