title: Fused Bicyclic Caspase-1 Inhibitors Assembled by Copper-Free Strain-Promoted Alkyne-Azide Cycloaddition (SPAAC).
abstract: Challenges exist in the development of potent and selective small-molecule inhibitors against caspase-1. Herein, by making use of the copper-free strain-promoted alkyne-azide cycloaddition (SPAAC) reaction between difluorinated cyclooctynes (DIFOs) and various azide-containing compounds, we showed for the first time that potential caspase-1 inhibitors could be rapidly synthesized. The resulting fused bicyclic compounds structurally resembled the central portion (P2-P3) of Pralnacasan (a well-known small molecule caspase-1 inhibitor), with diversity at the P4-position of the parental inhibitor conveniently installed from the azide component. Since our SPAAC-assembled inhibitor library was synthesized by using a copper-free bioorthogonal chemistry, the resulting 52-membered library (2 DIFOs×26 azides) was immediately ready for subsequent cell-based screening for rapid identification of potential cell-permeable hits capable of effectively inhibiting endogenous caspase-1 activities. C1FS, a recently reported fluorogenic two-photon probe, which possesses improved live-cell imaging sensitivity against endogenous caspase-1, was used both in vitro and in LPS/ATP-induced macrophages (a well-established caspase-1-activated cell model) to screen against selected compounds from the above-mentioned library, leading to subsequent discovery of a novel caspase-1 inhibitor named b7-b.
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Linghui
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Chong-Jing
authors.initials: CJ
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Ji'en
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543, Singapore.
authors.forename: Shao Q
authors.initials: SQ
authors.lastname: Yao
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000818:Animals; D001381:Azepines / Q000737:chemistry; D001386:Azides / Q000737:chemistry*; D020170:Caspase 1 / Q000737:chemistry*; D061945:Caspase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D061565:Cycloaddition Reaction; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D007546:Isoquinolines / Q000737:chemistry; D051379:Mice; D011724:Pyridazines / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D001381:Azepines; D001386:Azides; D061945:Caspase Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D007546:Isoquinolines; D011724:Pyridazines; D054852:Small Molecule Libraries; D020170:Caspase 1; C476331:pralnacasan
keywords: bioorthogonal chemistry; caspase-1; copper-free synthesis; drug discovery; small-molecule inhibitor