Ruthenium-based PACT agents based on bisquinoline chelates: synthesis, photochemistry, and cytotoxicity

The known ruthenium complex [Ru(tpy)(bpy)(Hmte)](PF6)(2) ([1](PF6)(2), where tpy = 2,2':6',2 ''-terpyridine, bpy = 2,2'-bipyridine, Hmte = 2-(methylthio)ethanol) is photosubstitutionally active but non-toxic to cancer cells even upon light irradiation. In this work, the two analogs complexes [Ru(tpy)(NN)(Hmte)](PF6)(2), where NN = 3,3'-biisoquinoline (i-biq, [2](PF6)(2)) and di(isoquinolin-3-yl)amine (i-Hdiqa, [3](PF6)(2)), were synthesized and their photochemistry and phototoxicity evaluated to assess their suitability as photoactivated chemotherapy (PACT) agents. The increase of the aromatic surface of [2](PF6)(2) and [3](PF6)(2), compared to [1](PF6)(2), leads to higher lipophilicity and higher cellular uptake for the former complexes. Such improved uptake is directly correlated to the cytotoxicity of these compounds in the dark: while [2](PF6)(2) and [3](PF6)(2) showed low EC50 values in human cancer cells, [1](PF6)(2) is not cytotoxic due to poor cellular uptake. While stable in the dark, all complexes substituted the protecting thioether ligand upon light irradiation (520 nm), with the highest photosubstitution quantum yield found for [3](PF6)(2) (phi([3]) = 0.070). Compounds [2](PF6)(2) and [3](PF6)(2) were found both more cytotoxic after light activation than in the dark, with a photo index of 4. Considering the very low singlet oxygen quantum yields of these compounds, and the lack of cytotoxicity of the photoreleased Hmte thioether ligand, it can be concluded that the toxicity observed after light activation is due to the photoreleased aqua complexes [Ru(tpy)(NN)(OH2)](2+), and thus that [2](PF6)(2) and [3](PF6)(2) are promising PACT candidates.[GRAPHICS].Metals in Catalysis, Biomimetics & Inorganic Material

Alkyne Functionalization of a Photoactivated Ruthenium Polypyridyl Complex for Click-Enabled Serum Albumin Interaction Studies

Studying metal-protein interactions is key for understanding the fate of metallodrugs in biological systems. When a metal complex is not emissive and too weakly bound for mass spectrometry analysis, however, it may become challenging to study such interactions. In this work a synthetic procedure was developed for the alkyne functionalization of a photolabile ruthenium polypyridyl complex, [Ru(tpy)(bpy)(Hmte)](PF6)2, where tpy = 2,2′:6′,2′′-terpyridine, bpy = 2,2′-bipyridine, and Hmte = 2-(methylthio)ethanol. In the functionalized complex [Ru(HCC-tpy)(bpy)(Hmte)](PF6)2, where HCC-tpy = 4′-ethynyl-2,2′:6′,2′′-terpyridine, the alkyne group can be used for bioorthogonal ligation to an azide-labeled fluorophore using copper-catalyzed “click” chemistry. We developed a gel-based click chemistry method to study the interaction between this ruthenium complex and bovine serum albumin (BSA). Our results demonstrate that visualization of the interaction between the metal complex and the protein is possible, even when this interaction is too weak to be studied by conventional means such as UV–vis spectroscopy or ESI mass spectrometry. In addition, the weak metal complex-protein interaction is controlled by visible light irradiation, i.e., the complex and the protein do not interact in the dark, but they do interact via weak van der Waals interactions after light activation of the complex, which triggers photosubstitution of the Hmte ligand.Metals in Catalysis, Biomimetics & Inorganic MaterialsBio-organic Synthesi

Physically active academic lessons; Acceptance, barriers and facilitators for implementation

Background To improve health and academic learning in schoolchildren, the Active School programme in Stavanger, Norway has introduced physically active academic lessons. This is a teaching method combining physical activity with academic content. The purpose of this paper was to evaluate the response to the physically active lessons and identify facilitators and barriers for implementation of such an intervention. Methods Five school leaders (principals or vice-principals), 13 teachers and 30 children from the five intervention schools were interviewed about their experiences with the 10-month intervention, which consisted of weekly minimum 2 × 45 minutes of physically active academic lessons, and the factors affecting its implementation. All interviews were transcribed and analysed using the qualitative data analysis program NVivo 10 (QSR international, London, UK). In addition, weekly teacher’s intervention delivery logs were collected and analysed. Results On average, the physically active academic lessons in 18 of the 34 weeks (53%) were reported in the teacher logs. The number of delivered physically active academic lessons covered 73% of the schools’ planned activity. Physically active lessons were well received among school leaders, teachers and children. The main facilitators for implementation of the physically active lessons were active leadership and teacher support, high self-efficacy regarding mastering the intervention, ease of organizing physically active lessons, inclusion of physically active lessons into the lesson curricula, and children’s positive reception of the intervention. The main barriers were unclear expectations, lack of knowledge and time to plan the physiclly active lessons, and the length of the physically active lessons (15–20 min lessons were preferred over the 45 min lessons). Conclusion Physically active academic lessons were considered an appropriate pedagogical method for creating positive variation, and were highly appreciated among both teachers and children. Both the principal and the teachers should be actively involved the implementation, which could be strengthened by including physical activity into the school’s strategy. Barriers for implementing physically active lessons in schools could be lowered by increasing implementation clarity and introducing the teachers to high quality and easily organized lessons.publishedVersio

School Effects on the Wellbeing of Children and Adolescents

Well-being is a multidimensional construct, with psychological, physical and social components. As theoretical basis to help understand this concept and how it relates to school, we propose the Self-Determination Theory, which contends that self-determined motivation and personality integration, growth and well-being are dependent on a healthy balance of three innate psychological needs of autonomy, relatedness and competence. Thus, current indicators involve school effects on children’s well-being, in many diverse modalities which have been explored. Some are described in this chapter, mainly: the importance of peer relationships; the benefits of friendship; the effects of schools in conjunction with some forms of family influence; the school climate in terms of safety and physical ecology; the relevance of the teacher input; the school goal structure and the implementation of cooperative learning. All these parameters have an influence in promoting optimal functioning among children and increasing their well-being by meeting the above mentioned needs. The empirical support for the importance of schools indicates significant small effects, which often translate into important real-life effects as it is admitted at present. The conclusion is that schools do make a difference in children’s peer relationships and well-being

Alkyne Functionalization of a Photoactivated Ruthenium Polypyridyl Complex for Click-Enabled Serum Albumin Interaction Studies

Studying metal-protein interactions is key for understanding the fate of metallodrugs in biological systems. When a metal complex is not emissive and too weakly bound for mass spectrometry analysis, however, it may become challenging to study such interactions. In this work a synthetic procedure was developed for the alkyne functionalization of a photolabile ruthenium polypyridyl complex, [Ru(tpy)(bpy)(Hmte)](PF6)2, where tpy = 2,2':6',2''-terpyridine, bpy = 2,2'-bipyridine, and Hmte = 2-(methylthio)ethanol. In the functionalized complex [Ru(HCC-tpy)(bpy)(Hmte)](PF6)2, where HCC-tpy = 4'-ethynyl-2,2':6',2''-terpyridine, the alkyne group can be used for bioorthogonal ligation to an azide-labeled fluorophore using copper-catalyzed "click" chemistry. We developed a gel-based click chemistry method to study the interaction between this ruthenium complex and bovine serum albumin (BSA). Our results demonstrate that visualization of the interaction between the metal complex and the protein is possible, even when this interaction is too weak to be studied by conventional means such as UV-vis spectroscopy or ESI mass spectrometry. In addition, the weak metal complex-protein interaction is controlled by visible light irradiation, i.e., the complex and the protein do not interact in the dark, but they do interact via weak van der Waals interactions after light activation of the complex, which triggers photosubstitution of the Hmte ligand

On the Problem of Evaluating Quasistationary Distributions for Open Reaction Schemes

A number of recent papers have been concerned with the stochastic modeling of autocatalytic reactions. In some instances the birth and death model has been criticized for its apparent inadequacy in being able to describe the long-term behavior of the catalyst, in particular the fluctuations in the concentration of the catalyst about its macroscopically stable state. This criticism has been answered, to some extent, with the introduction of the notion of a quasistationary distribution; a number of authors have established the existence of limiting conditional distributions that can adequately describe these fluctuations. However, much of the work appears only to be appropriate for dealing with closed systems, for attention is usually restricted to finite-state birth and death processes. For open systems it is more appropriate to consider infinite-state processes and, from the point of view of establishing conditions for the existence of quasistationary distributions, extending the results for closed systems is far from straightforward. Here, simple conditions are given for the existence of quasistationary distributions for Markov processes with a denumerable infinity of states. These can be applied to any open autocatalytic system. The results also extend to explosive processes and to processes that terminate with probability less than 1