Publications by authors named "Shea L Johnson"

4 Publications

  • Page 1 of 1

A Series of 2-((1-Phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

ChemMedChem 2021 Jul 26;16(14):2195-2205. Epub 2021 May 26.

Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC =0.16 μM, EC =0.3 μM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.
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http://dx.doi.org/10.1002/cmdc.202100107DOI Listing
July 2021

Organocatalytic Olefin Aziridination via Iminium-Catalyzed Nitrene Transfer: Scope, Limitations, and Mechanistic Insight.

J Org Chem 2019 07 19;84(13):8589-8595. Epub 2019 Jun 19.

Department of Chemistry , University of Virginia , Charlottesville , Virginia 22904-4319 , United States.

Olefin aziridination via organocatalytic nitrene transfer offers potential complementarity to metal-catalyzed methods; however there is a lack of reports of such reactions in the literature. Herein is reported a method that employs an iminium salt to catalyze the aziridination of styrenes by [ N-( p-toluenesulfonyl)imino]phenyliodinane (PhINTs). These reactions are hypothesized to proceed via a diaziridinium salt as the active oxidant. In addition to outlining the scope and limitations of the method, evidence for a polar, stepwise mechanism is presented, which provides new insight into the nature of iminium catalysis of nitrene transfer.
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http://dx.doi.org/10.1021/acs.joc.9b01023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008636PMC
July 2019

Rh(II)-Catalyzed Nitrene-Transfer [5 + 1] Cycloadditions of Aryl-Substituted Vinylcyclopropanes.

Org Lett 2019 04 25;21(7):2307-2311. Epub 2019 Mar 25.

Department of Chemistry , University of Virginia , Charlottesville , Virginia 22904-4319 , United States.

Formal [5 + 1] cycloadditions between aryl-substituted vinylcyclopropanes and nitrenoid precursors are reported. The method, which employs Rh(esp) as a catalyst, leads to the highly regioselective formation of substituted tetrahydropyridines. Preliminary mechanistic studies support a stepwise, polar mechanism enabled by the previously observed Lewis acidity of Rh-nitrenoids. Overall, this work expands the application of nitrene-transfer cycloaddition, a relatively underexplored approach to heterocycle synthesis, to the formation of six-membered rings.
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http://dx.doi.org/10.1021/acs.orglett.9b00594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492922PMC
April 2019

Organocatalytic, Dioxirane-Mediated C-H Hydroxylation under Mild Conditions Using Oxone.

Org Lett 2017 09 25;19(18):4790-4793. Epub 2017 Aug 25.

Department of Chemistry, University of Virginia , Charlottesville, Virginia 22904-4319, United States.

Dioxiranes are among the most selective and useful reagents for C(sp)-H hydroxylation, but the development of a general dioxirane-mediated catalytic method has been an elusive goal. A trifluoromethyl ketone catalyst in combination with Oxone is shown to enable the first dioxirane-mediated catalytic hydroxylations that approximate the reactivity and selectivity of isolated dioxiranes. The mild reaction conditions allow for selective 3° hydroxylation and 2° oxidation and are tolerant of acid-sensitive functionality and electron-neutral arenes.
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http://dx.doi.org/10.1021/acs.orglett.7b02178DOI Listing
September 2017
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