Highly Enantioselective Catalytic Vinylogous Propargylation of Coumarins Yields a Class of Autophagy Inhibitors

Abstract

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New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems

“…Substituted methyl-cyanocoumarins 767 were also exploited by Antonchick, Waldmann, et al as suitable pronucleophiles in a highly enantioselective copper-catalyzed vinylogous propargylic substitution, which afforded enantioenriched propargylic coumarins of type 771 , which were also studied as autophagy inhibitors ( Scheme 196 , eq 2). 509 Aromatic and aliphatic propargylic esters 770 reacted smoothly with substituted coumarins 767 under the guidance of the Cu(OTf) 2 / L26 catalytic system, to give the desired products with excellent yields (up to 96%) and enantioselectivities (up to 98% ee).…”

Thermal proteome profiling identifies the membrane-bound purinergic receptor P2X4 as a target of the autophagy inhibitor indophagolin

“…Because of the important role of autophagy in disease (Levine and Kroemer, 2008;Rubinsztein et al, 2012), a series of phenotypic assays to detect autophagic activity have been developed over the past decade, which have led to the discovery of multiple novel modulators of this cellular program. Moreover, many of these assays have been successfully employed as the starting point for target identification campaigns (Cho and Kwon, 2010;Galluzzi et al, 2017;Kaiser et al, 2019;Laraia et al, 2017;Laraia et al 2019;Robke et al, 2018;Robke et al, 2017;Rubinsztein et al, 2012;Towers and Thorburn, 2016;Xu et al, 2017). Thus, for identification of new autophagy inhibitors, we selected an established phenotypic assay for autophagy inhibition that uses the human breast cancer cell line MCF7, stably expressing enhanced green fluorescent protein (eGFP) tagged to microtubule-associated protein light chain 3 (LC3) as a marker for autophagosome formation, as previously described Kaiser et al, 2019;Laraia et al, 2017;Robke et al, 2018;Robke et al, 2017;Xu et al, 2017).…”

“…Moreover, many of these assays have been successfully employed as the starting point for target identification campaigns (Cho and Kwon, 2010;Galluzzi et al, 2017;Kaiser et al, 2019;Laraia et al, 2017;Laraia et al 2019;Robke et al, 2018;Robke et al, 2017;Rubinsztein et al, 2012;Towers and Thorburn, 2016;Xu et al, 2017). Thus, for identification of new autophagy inhibitors, we selected an established phenotypic assay for autophagy inhibition that uses the human breast cancer cell line MCF7, stably expressing enhanced green fluorescent protein (eGFP) tagged to microtubule-associated protein light chain 3 (LC3) as a marker for autophagosome formation, as previously described Kaiser et al, 2019;Laraia et al, 2017;Robke et al, 2018;Robke et al, 2017;Xu et al, 2017). The screen identified the indoline derivative indophagolin (1; Figure 1A) as a potent inhibitor of autophagy (IC 50 = 140 ± 40 nM; Figures 1B and 1C; Table 1) among our in-house compound collection of approximately 160,000 compounds.…”

Bioactive Compound Collections: From Design to Target Identification

“…(Figure 13B). Recently, a new inhibitor chemotype for the lipid kinase VPS34, 45 a cinchona alkaloid derivative that acts via a dual mode of action, 22 a coumarin with an as yet unknown target, 58 and a deubiquitinase inhibitor were identified (Figure 13C). 59 In addition to screening for a specific phenotype, multiparameter imaging or profiling can be used to assess biological activity and diversity in a very general sense and to identify potential targets by similarity to known reference compounds.…”