title: Tagging the Untaggable: A Difluoroalkyl-Sulfinate Ketone-Based Reagent for Direct C-H Functionalization of Bioactive Heteroarenes.
abstract: We have developed a new difluoroalkyl ketal sulfinate salt reagent suitable for direct derivatization of heteroarene C-H bonds. The reagent is capable of introducing a ketone functional group on heteroarene bioactive compounds via a one-pot reaction. Remarkably, in three examples the ketone analog and its parent drug had almost identical cytotoxicity. In a representative example, the ketone analog was bioconjugated with a delivery vehicle via an acid-labile semicarbazone linkage and with a photolabile protecting group to produce the corresponding prodrug. Controlled release of the drug-ketone analog was demonstrated in vitro for both systems. This study provides a general approach to obtain taggable ketone analogs directly from bioactive heteroarene compounds with limited options for conjugation. We anticipate that this sodium ketal-sulfinate reagent will be useful for derivatization of other heteroarene-based drugs to obtain ketone-taggable analogs with retained efficacy.
authors: Samer
authors: S
authors: Gnaim
authors: Anna
authors: A
authors: Scomparin
authors: Xiuling
authors: X
authors: Li
authors: Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors: Phil S
authors: PS
authors: Baran
authors: Christoph
authors: C
authors: Rader
authors: Ronit
authors: R
authors: Satchi-Fainaro
authors: Doron
authors: D
authors: Shabat
mesh_terms: D001554:Benzene / Q000737:chemistry*; D002244:Carbon / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006859:Hydrogen / Q000737:chemistry*; D007202:Indicators and Reagents / Q000737:chemistry; D007659:Ketones / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D013441:Sulfinic Acids / Q000737:chemistry*
chemical_list: D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D007659:Ketones; D013441:Sulfinic Acids; D002244:Carbon; D006859:Hydrogen; D001554:Benzene