Interactive teaching with larger groups of students can be a challenge, but the use of mobile electronic devices by students (smartphones, tablets, laptops) can be used to improve classroom interaction. We have examined several types of tasks that can be electronically enacted in classes and practical courses using these devices: multiple choice (MC) questions; open-ended questions; and 3D visualization of (bio)molecules and complexes. We have introduced these tasks dynamically in several educational contexts in our teaching programs. Specifically, attention is paid to applying devices in introductory quizzes at the start of a course, throughout lectures, and in practical courses. Each application has been found by us to offer significant merits in terms of connecting theory and practice, full formative assessment (including an improvement in interactions of introverted students), monitoring progress, engaging students early on in research, stimulating “3D” molecular feeling, and maintaining student attention. From the student perspective, evaluations revealed overall positive feedback on several key aspects of our approaches. In all, we believe that this mutually beneficial way of teaching can be of broader application, also in nonchemistry-related curricula.Keywords: Drugs/Pharmaceuticals; First-Year Undergraduate/General; High School/Introductory Chemistry; Internet/Web-Based Learning; Medicinal Chemistry; Molecular Modeling; Second-Year Undergraduate; Testing/Assessment; Upper-Division Undergraduate;

Hydroxy-aryl-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles represent interesting chemical scaffolds, but synthetic access to these compounds is limited. The reaction of 2-aroyl-cyclohexanones with 2-cyanoacetamide and base in ethanol has been reported to lead to the formation of the tetrahydroisoquinoline isomer. We show that depending on the electronic nature of the para-substituent on the aryl ring, formation of the regioisomeric tetrahydroquinoline isomer can significantly compete. The electron-donating or -withdrawing properties of the para-substituent of the aryl ring determines the ratio of product isomers. A series of 2-aroyl-cyclohexanones, with para-substituents ranging from electron-donating to electron-withdrawing, were reacted with [2-13C]-cyanoacetamide. The product ratio and absolute regiochemistry were directly determined by quantitative 13C, HMBC, and NOESY NMR spectroscopy on the reaction mixtures. A clear relationship between the regioisomeric product ratio and the Hammett sigma values of the substituents is demonstrated. This is explained by the separate in situ yields, which reveal that the pathway leading to the tetrahydroquinoline regioisomer is significantly more sensitive toward the electronic nature of the para-substituent than the pathway leading to the tetrahydroisoquinoline. Semiempirical AM1 molecular orbital calculations on the starting electrophile 2-aroyl-cyclohexanone support a correlation between the energy of the LUMOs and the regioisomeric product ratio. Our results facilitate synthetic access to a range of these interesting synthetic intermediates.

The histamine H3 (H3R) and H4 (H4R) receptors attract considerable interest from the medicinal chemistry community. Given their relatively high homology yet widely differing therapeutic promises, ligand selectivity for the two receptors is crucial. We interrogated H4R/H3R selectivities using ligands with a [1,2,3]triazole core. Cu(I)-assisted “click chemistry” was used to assemble diverse [1,2,3]triazole compounds (6a−w and 7a−f), many containing a peripheral imidazole group. The imidazole ring posed some problems in the click chemistry putatively due to Cu(II) coordination, but Boc protection of the imidazole and removal of oxygen from the reaction mixture provided effective strategies. Pharmacological studies revealed two monosubstituted imidazoles (6h,p) with <10 nM H4R affinities and >10-fold H4R/H3R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H4R with high steric precision. The use of the [1,2,3]triazole scaffold is further demonstrated by the notion that simple changes in spacer length or peripheral groups can reverse the selectivity toward H3R. Computational evidence is provided to account for two key selectivity switches and to pinpoint a lipophilic pocket as an important handle for H4R over H3R selectivity.

Targeting of chemokine receptors by small molecules has been widely pursued. This review highlights recent illustrative disclosures of clinical relevance that could further shape our appreciation, and add to our understanding, of the therapeutic value of chemokine receptor targeting. Disclosures include new structures, announcements of new trials, or results of conducted trials (including setbacks). This review shows how most of the discussed disclosures seem to be concentrated on selected receptors, for example, CCR1, CCR2, CCR5, CCR9, CXCR2 and CXCR4, with a wide variety of associated ligand chemotypes and diseases. With two approved antagonist drugs and several in Phase III trials, as well as new antagonist chemotypes entering the pipeline, the chemokine receptor field proves dynamic and upcoming results will further fuel the field.Download high-res image (229KB)Download full-size image