title: Convergent synthesis and discovery of a natural product-inspired paralog-selective Hsp90 inhibitor.
abstract: A convergent synthesis of benzoquinone ansamycin analogs is described that proceeds by a sequence of metallacycle-mediated alkyne-alkyne coupling, followed by site- and stereoselective dihydroxylation and global carbamate formation. These studies have led to (1) validation of alkyne-alkyne coupling to produce geldanamycin analogs that lack the problematic quinone, (2) the discovery that C6-C7 bis-carbamate functionality is compatible with Hsp90 inhibition, and (3) the identification of 1 as a nonquinone geldanamycin-inspired paralog-selective Hsp90 inhibitor.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Valer
authors.initials: V
authors.lastname: Jeso
authors.forename: Lisa
authors.initials: L
authors.lastname: Cherry
authors.forename: Todd K
authors.initials: TK
authors.lastname: Macklin
authors.forename: Subhas Chandra
authors.initials: SC
authors.lastname: Pan
authors.forename: Philip V
authors.initials: PV
authors.lastname: LoGrasso
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Micalizio
mesh_terms: D016227:Benzoquinones / Q000737:chemistry*; D001688:Biological Products / Q000138:chemical synthesis* / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D016227:Benzoquinones; D001688:Biological Products; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C004532:quinone