Kinetics and Mechanism of Hydrolysis of Benzimidazolylcarbamates

Synthesis of new 2-aminobenzimidazole-1-carbamates was accomplished by carbamoylation of 2-aminobenzimidazole using different substituted phenyl chloroformates. The aqueous hydrolysis of the new compounds was examined in the pH range 1-13 at 25 oC. The evaluated kinetic parameters led to the conclusion that up to pH 4 reaction proceeds by a bimolecular attack of water to the N-protonated substrate. This is the first time this behavior is described for carbamates, and can be ascribed to the higher basicity of the benzimidazolyl moiety when compared with the carbonyl oxygen. For higher values of pH, the results are consistent with a BAc2 mechanism with nucleophilic catalysis, but while between pH 4 and pH 7 water acts as the nucleophile, for pH> 7 the hydroxide ion is the acting species

Synthesis of some new 2-heterosubstituted 4,5-dihydroimidazoles

Several new 4,5-dihydroimidazoles (and the corresponding imidazolium salts) carrying heteroatom substituents at C-2 have been prepared from the corresponding tetrahydroimidazol-2-ones and/or -thiones

Smoking and Blindness What Optometrists Want their Patients to See

Most smokers are not aware that their tobacco use is a preventable cause of blindness. Despite the important role optometrists can have impacting patient health choices; their voice has been largely silent in the development of tobacco cessation practice guidelines and health promotion strategies. In this study, we use the International Tobacco Control Policy Evaluation Project (ITC) Four Country Survey to describe the level of Canadian smokers’ knowledge of the association of smoking with blindness and we use focus groups to elicit ideas from Canadian optometrists and senior optometry students about blindness-related graphic warning labels

Dopamine- and tyramine-based derivatives of triazenes. Activation by tyrosinase and implications for prodrug design

We report the synthesis of triazene derivatives, and their evaluation as substrates for tyrosinase. The conversion of prodrugs to the ortho-quinone was confirmed by LC-MS

Le tabagisme et la cécité : ce que les optométristes veulent faire voir à leurs patients

La plupart des fumeurs ne savent pas que le tabagisme constitue une cause évitable de cécité. Même si les optométristes peuvent jouer un rôle important dans les choix santé des patients, ils ont été en grande partie muets dans l’élaboration des guides de pratique sur l’abandon du tabac et les stratégies de promotion de la santé. Au cours de cette étude, nous utilisons l’enquête réalisée dans quatre pays dans le cadre du Projet d’évaluation à l’échelon international des politiques antitabac (ITC) pour décrire dans quelle mesure les fumeurs du Canada connaissent le lien entre le tabagisme et la cécité. Nous utilisons des groupes de discussion pour dégager, chez des optométristes et des étudiants finissants en optométrie du Canada, des idées au sujet de mises en garde illustrées reliées à la cécité

Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line

Recently, with the purpose of enhancing the potency of epidermal growth factor receptor (EGFR)-based therapies, we designed a novel strategy termed ‘Cascade-release targeting’ that seeks to develop molecules capable of degrading to multiple tyrosine kinase (TK) inhibitors and highly reactive electrophiles, in a stepwise fashion. Here we report on the first prototype of this model, RB24, a masked methyltriazene, that in addition to being an inhibitor on its own was designed to degrade to RB14, ZR08, RB10+a DNA alkylating methyldiazonium species. The cascade degradation of RB24 requires the generation of two reactive electrophiles: (a) an iminium ion and (b) a methyldiazonium ion. Thus, we surmise that these species could alkylate the active site of EGFR, thereby irreversibly blocking its action and that DNA damage could be induced by the methyldiazonium. Using the EGFR-overexpressing human epidermoid carcinoma of the vulva cell line, A431, we demonstrate herein that (a) RB24 and its derived species (e.g. RB14, ZR08) irreversibly inhibit EGFR autophosphorylation, (b) RB24 induced significant levels of DNA strand breaks, (c) sustained inhibition of EGFR by RB24 was associated with blockade of MAPK activation and c-fos gene expression, (d) RB24 induced irreversible cell growth inhibition with a 100-fold greater potency than Temodal™, a clinical methyltriazene. The pronounced growth inhibitory potency of RB24 was attributed to its ability to simultaneously damage DNA and irreversibly block EGFR TK activity

Regulation of voltage-gated sodium channel expression in cancer : hormones, growth factors and auto-regulation

Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na(+) channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional channel expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC expression and regulation in cancer

Teaching open and reproducible scholarship: a critical review of the evidence base for current pedagogical methods and their outcomes

In recent years, the scientific community has called for improvements in the credibility, robustness and reproducibility of research, characterized by increased interest and promotion of open and transparent research practices. While progress has been positive, there is a lack of consideration about how this approach can be embedded into undergraduate and postgraduate research training. Specifically, a critical overview of the literature which investigates how integrating open and reproducible science may influence student outcomes is needed. In this paper, we provide the first critical review of literature surrounding the integration of open and reproducible scholarship into teaching and learning and its associated outcomes in students. Our review highlighted how embedding open and reproducible scholarship appears to be associated with (i) students' scientific literacies (i.e. students’ understanding of open research, consumption of science and the development of transferable skills); (ii) student engagement (i.e. motivation and engagement with learning, collaboration and engagement in open research) and (iii) students' attitudes towards science (i.e. trust in science and confidence in research findings). However, our review also identified a need for more robust and rigorous methods within pedagogical research, including more interventional and experimental evaluations of teaching practice. We discuss implications for teaching and learning scholarship