title: Synthesis of the 2-methylene analogue of the HRV 3C protease inhibitor thysanone (2-carbathysanone).
abstract: The Human Rhinovirus (HRV) is the major aetiological agent for the common cold, for which only symptomatic treatment is available. HRV maturation and replication is entirely dependent on the activity of a virally encoded 3C protease that represents an attractive target for the development of therapeutics to treat the common cold. Herein we report the synthesis and biological evaluation of the 2-methylene analogue of the HRV 3C protease inhibitor (-)-thysanone (1) namely 2-carbathysanone (2), in an attempt to decipher the structural features in the natural product that are responsible for the 3C protease activity. 2-Carbathysanone (2) (and related analogues (±)-cis-23, (±)-cis-30, (±)-31) did not inhibit HRV 3C protease, indicating that the lactol functionality present in (-)-thysanone (1) is a critical structural feature required for inhibition.
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds St., Auckland, New Zealand. m.brimble@auckland.ac.nz.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schünemann
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Furkert
authors.forename: Eun Cho
authors.initials: EC
authors.lastname: Choi
authors.forename: Stephen
authors.initials: S
authors.lastname: Connelly
authors.forename: John D
authors.initials: JD
authors.lastname: Fraser
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sperry
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
mesh_terms: D000086042:3C Viral Proteases; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D009285:Naphthoquinones; D011480:Protease Inhibitors; D014764:Viral Proteins; C000592476:thysanone; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases