title: Unexpected stereochemical tolerance for the biological activity of tyroscherin.
abstract: Here we describe the concise syntheses of the 15 diastereomers and key analogs of the natural product tyroscherin. While systematic analysis of the analogs clearly demonstrated that the hydrocarbon tail is important for biological activity, structure-activity relationship studies of the complete tyroscherin diastereoarray revealed a surprisingly expansive stereochemical tolerance for the cytotoxic activity. Our results represent a departure from the tenet that biological activity is constrained to a narrow pharmacophore, and highlight the recently emerging appreciation for stereochemical flexibility in defining the essential structural elements of biologically active small molecules.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Hyun Seop
authors.initials: HS
authors.lastname: Tae
authors.forename: John
authors.initials: J
authors.lastname: Hines
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Schneekloth
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004837:Epinephrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005233:Fatty Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005233:Fatty Alcohols; C495800:tyroscherin; D004837:Epinephrine