ABSTRACT
This article examines the ways that a shared faculty experience across five partner institutions led to a deep awareness of the curriculum and pedagogy of general chemistry coursework, and ultimately, to a collaborative action plan for student success. The team identified key differences and similarities in course content and instructional experiences. The comparative analysis yielded many more similarities than differences, and therefore, the team shifted its focus from "gap analysis" to an exploration of common curricular challenges. To address these challenges, the team developed content for targeted instructional resources that promoted the success of all STEM students across institutions. This article contextualizes the interinstitutional collaboration and closely examines the interactive components (awareness, analysis, and action), critical tools, and productive attitudes that undergirded the curricular alignment process of the STEM Transfer Student Success Initiative (t-STEM).
ABSTRACT
The syntheses of stereodiverse libraries of 12 and 19 are reported, where each asterisk represents an independently varied stereocenter. These scaffolds provide additional templates for investigations of geometric diversity in library syntheses. Libraries of these N-Fmoc-amino acids were further functionalized by incorporation into a peptide sequence, demonstrating the utility of 12 and 19 as building blocks for diversity oriented synthesis.
Subject(s)
Amino Acids/chemistry , Combinatorial Chemistry Techniques/methods , Fluorenes/chemistry , Oligopeptides/chemical synthesis , Alcohols/chemistry , Alkenes/chemistry , Amino Acids/chemical synthesis , Fluorenes/chemical synthesis , Formic Acid Esters/chemistry , Leucine/chemistry , Oligopeptides/chemistry , StereoisomerismABSTRACT
In this communication, we report the synthesis of an exhaustively stereodiversified library of 16 1,5-enediols (2) and the screening of these compounds for mu opioid receptor (MOR) binding. The stereochemical configuration of 2 strongly impacted the binding affinity, and (S,S,S,R)-2 exhibited a Ki of 8.8 nM for MOR, comparable to that of endomorphin-2 (Ki = 1.2 nM). Moreover, compounds 2 exhibited 5-86-fold selectivity for MOR over delta opioid receptor (DOR) and 16-150-fold selectivity for MOR over kappa opioid receptor (KOR). Additionally, analogues of 2 were synthesized which showed the importance of the trans olefin for receptor binding but that modifications of the C-terminal amino acid were well tolerated. Ligand 11 is noteworthy because it retains only one of the amide bonds present in 1, but binds MOR with an affinity of 10 nM and 110- and 600-fold selectivity for MOR over DOR and KOR. These results demonstrate the utility of stereochemical diversity in the discovery of bioactive small molecules.
Subject(s)
Alcohols/metabolism , Alkenes/metabolism , Receptors, Opioid, mu/metabolism , Alcohols/chemistry , Alcohols/pharmacology , Alkenes/chemistry , Alkenes/pharmacology , Combinatorial Chemistry Techniques , Dipeptides/chemistry , Dipeptides/metabolism , Dipeptides/pharmacology , Kinetics , Ligands , Receptors, Opioid, delta/chemistry , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/chemistry , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
A conformational analysis of a stereochemically complete set of peptide analogues based on a cis-enediol unit is presented. The cis-enediol unit, which can replace a two or a three amino acid segment of a peptide, contains two "side chains", four asymmetrical carbon atoms, and six free dihedral angles. To determine the accessible conformational space, the molecules are divided into three fragments, each containing two free dihedral angles. The energy surfaces are computed for all dihedral angle values, and the possible conformations of the cis-enediol unit analogues are built using all combinations of the surface minima. Such a "build-up" procedure, which is very fast, is able to reproduce 75% of the minima obtained from a full dihedral angle exploration of the conformational space. The cis-enediol unit minima are compared with the corresponding di- and tripeptide minima; all peptide minima can be closely matched by a cis-enediol unit minimum of low energy (less than 2.2 kcal/mol above the lowest energy conformer). However, there are low energy minima of the cis-enediol unit that have no corresponding minima in peptides. The results are shown to depend strongly on the chirality of the analogues. The ability of each of the stereoisomers to mimic natural peptides, evaluated by the present approach, is correlated with its experimental activity in a renin inhibition assay.
