RESUMEN
Methods for rapid preparation of densely functionalized and stereochemically complex N-heterocyclic scaffolds are in demand for exploring potential bioactive chemical space. This work describes experimental and computational studies to better understand the features of aziridinium ylides as intermediates for the synthesis of highly substituted dehydromorpholines. The development of this chemistry has enabled the extension of aziridinium ylide chemistry to the concomitant formation of both a C-N and a C-O bond in a manner that preserves the stereochemical information embedded in the substrate. Additionally, we have uncovered several key insights that describe the importance of steric effects, rotational barriers around the C-N bond of the aziridinium ylide, and non-covalent interactions (NCIs) on the ultimate reaction outcome. These critical insights will assist in the further development of this chemistry to generate N-heterocycles that will further expand complex amine chemical space.
RESUMEN
Antimicrobial peptides (AMPs) show promise for the treatment of bacterial infections, but many have undesired hemolytic activities. The AMP MP1 not only has broad spectrum bactericidal activity, but has been shown to have antitumor activity. The interaction between AMPs and cellular membranes gives rise to a peptide's cell-specificity and activity. However, direct analysis of the biophysical interactions between peptides and membrane is complex, in part due to the nature of membrane environments as well as structural changes in the peptide that occurs upon binding to the membrane. In order to investigate the interplay between cell selectivity, activity, and secondary structural changes involved in antimicrobial peptide activity, we sought to implement photolizable membrane mimics to assess the types of information available from infrared spectroscopic measurements that follow from photoinitiated peptide dynamics. Azo-surfactants (APEG) form micelles containing a photolizable azobenzene core, which upon irradiation can induce membrane deformation resulting in breakdown of micelles. Spectroscopic analysis of membrane deformation may provide insights into the physical behavior associated with unfolding and dissociation of antimicrobial peptides within a membrane environment. Herein, we synthesized and characterized two new azo-surfactants, APEGTMG and APEGNEt2MeI. Furthermore, we demonstrate the viability of azosurfactants as membrane mimics by examining both the membrane binding and dissociation induced secondary structural changes of the antimicrobial peptide, MP1.