title: Synthesis of a 35-member stereoisomer library of bistramide A: evaluation of effects on actin state, cell cycle and tumor cell growth.
abstract: Synthesis and preliminary biological evaluation of a 35-member library of bistramide A stereoisomers are reported. All eight stereoisomers of the C1-C13 tetrahydropyran fragment of the molecule were prepared utilizing crotylsilane reagents 9 and 10 in our [4+2]-annulation methodology. In addition, the four isomers of the C14-C18 gamma-amino acid unit were accessed via a Lewis acid mediated crotylation reaction with use of both enantiomers of organosilane 11. The spiroketal subunit of bistramide A was modified at the C39-alcohol to give another point of stereochemical diversification. The fragments were coupled by using a standard peptide coupling protocol to provide 35 stereoisomers of the natural product. These stereochemical analogues were screened for their effects on cellular actin and cytotoxicity against cancer cell lines (UO-31 renal and SF-295 CNS). The results of these assays identified one analogue, 1.21, with enhanced potency relative to the natural product, bistramide A.
authors.affiliation: Department of Chemistry and Center for Chemical Methodology and Library Development, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Iwona E
authors.initials: IE
authors.lastname: Wrona
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lowe
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Turbyville
authors.forename: Tanya R
authors.initials: TR
authors.lastname: Johnson
authors.forename: Julien
authors.initials: J
authors.lastname: Beignet
authors.forename: John A
authors.initials: JA
authors.lastname: Beutler
authors.forename: James S
authors.initials: JS
authors.lastname: Panek
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000199:Actins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000199:Actins; D000970:Antineoplastic Agents; D011714:Pyrans; D013141:Spiro Compounds; C059975:bistratene A