No abstract

Despite the ubiquity of singlet carbenes in chemistry, their utility as true monomeric building blocks for the synthesis of functional organic polymers has been underexplored. In this work, we exploit the capability of purposely designed mono- and bis-acyclic amino(aryl)carbenes to selectively dimerize as a general strategy to access diaminoalkenes and hitherto unknown amino-containing poly(p-phenylene vinylene)s (N-PPV’s). The unique selectivity of the dimerization of singlet amino(aryl)carbenes, relative to putative C-H insertion pathways, is rationalized by DFT calculations. Of particular interest, unlike classical PPV’s, the presence of amino groups in α-position of C=C double bonds in N-PPV’s allows their physico-chemical properties to be manipulated in different ways by a simple protonation reaction. Hence, depending on the nature of the amino group (iPr2N vs. piperidine), either a complete loss of conjugation or a blue-shift of the maximum of absorption is observed, as a result of the protonation at different sites (nitrogen vs. carbon). Overall, this study highlights that singlet bis-amino(aryl)carbenes hold great promise to access functional polymeric materials with switchable properties, through a proper selection of their substitution pattern.

Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of some diseases. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent inhibitors of the human mEH with IC50 values in the low nanomolar range, around 2 orders of magnitude more potent than previously obtained mEH inhibitors. Rationalization of binding through docking calculations of the inhibitors to a mEH homology model revealed that an acetamide, with a bulky aliphatic substituent at the α‐position, as well as an aryl ring 3–4 bonds away function as key pharmacophore units. No interaction was observed with the thioether moiety, suggesting it can be replaced by more metabolically stable (e.g. methylene) groups in future studies. Support or Funding Information National Institute of Health (NIH) R35 ES030443 and R01 GM076324‐11 grants; National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program P42 ES004699 grant; National Science Foundation Awards 1827246, 1805510 and 1627539; Computation support from Rosetta Commons and the US National Science Foundation’s XSEDE program Compound 62: The most potent mEH inhibitor Modeling of key molecular interactions in one binding mode. Left: interactions between amide group of 62 with D226, Y299 and Y374 side chain. Right: π–π stacking between 62 and W227.