This project is conducted by students during the second semester of their second year in our educational institution. This project constitutes an initiation into research and allows a broadening of knowledge, a development in autonomy, organization, team work, and initiative. It helps prepare the student-engineer for an internship in industry. The experiment is done in student pairs over 5 weeks (three, eight-hour days per week). We introduce experimental design to undergraduate students because such methodology is increasingly important in modern industrial research. The well-prepared chemist will need to apply these concepts easily. Other pedagogical goals include increasing experience in synthetic techniques, scientific rigor to obtain reproducibility in the yield, and using quantitative analysis methods. This project investigates optimizing the synthesis of benzyl-1-cyclopentan-1-ol using experimental design. It is carried out in three steps: first the factors that can have a potential influence on the reaction are screened; second, a factorial design is used to study the interactions between the factors; and finally, response surface methodology is used to optimize the yield.
Disrupting the interaction between the PDZ protein PSD-95 and the C-terminal domain of the 5-HT2A serotonin receptor has been shown to reduce hyperalgesia in a rodent model of neuropathic pain. Here, we designed and synthesized PDZ ligands capable of binding to the first PDZ domain (PDZ1) of the PSD-95 protein and evaluated their biological activity in vitro and in vivo. A series of substituted indoles was identified by docking simulations, and six novel analogues were synthesized. Three analogues displayed strong interactions with the first PDZ domain (PDZ1) of PDZ-95 in (1)H-(15)N heteronuclear single-quantum coherence (HSQC) experiments and two of them were able to inhibit the interaction between PSD-95 and the 5-HT2A receptor in vitro. We identified compound 8b as the analogue able to significantly suppress mechanical hyperalgesia in an experimental model of traumatic neuropathic pain in the rat. This effect was suppressed by the coadministration of the 5-HT2A receptor antagonist M100907, consistent with an inhibitory effect upon 5-HT2A receptor/PSD-95 interaction. Finally, we determined an NMR-restraint driven model structure for the PSD95 PDZ1/8b complex, which confirms that indole 8b binds to the putative PDZ-ligand binding site.
The aim of this experiment is to study and calculate the kinetic constant of a Heck reaction: the arylation of but-3-en-2-ol by iodobenzene catalyzed by palladium acetate in presence of triethylamine in DMF. The reaction leads to a mixture of two ketones. Students use GC analysis to quantify reagents and products of reaction. They control the global order of the reaction and prove that the two products are formed by two reactions that are in parallel. Finally, they calculate the rate constant for each reaction. Students calculate iodobenzene conversion, each product selectivity, yield, and catalyst turn over number (TON). These calculations are controlled using an internal standard, (-)-fenchone. This experiment is completed by students during their second-year kinetic laboratory and is done in pairs in a four-hour laboratory. This work allows students to work in the fields of organic and analytical chemistry, catalysis, and kinetics at the same time.
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