title: Facile diverted synthesis of pyrrolidinyl triazoles using organotrifluoroborate: discovery of potential mPTP blockers.
abstract: This article describes the rapid and diversified synthesis of pyrrolidinyl triazoles for the discovery of mitochondrial permeability transition pore (mPTP) blockers. The 1,3-dipolar cycloaddition of ethynyl trifluoroborate with azidopyrrolidine produced a key intermediate, triazolyl trifluoroborate 4, which subsequently underwent a Suzuki-Miyaura coupling reaction to afford a series of 1,4-disubstituted triazoles 2. Subsequent biological evaluation of these derivatives indicated 2ag and 2aj as the most potent mPTP blockers exhibiting excellent cytochrome P450 (CYP) stability when compared to the previously reported oxime analogue 1. The present work clearly demonstrates that a 1,2,3-triazole can be used as a stable oxime surrogate. Furthermore, it suggests that late-stage diversification through coupling reactions of organotrifluoroborates is suitable for the rapid discovery of biologically active molecules.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Sun hwa
authors.initials: Sh
authors.lastname: Jung
authors.forename: Kihang
authors.initials: K
authors.lastname: Choi
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.forename: Jae Kyun
authors.initials: JK
authors.lastname: Lee
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Sun-Joon
authors.initials: SJ
authors.lastname: Min
mesh_terms: D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011759:Pyrrolidines; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System