jo802269q_si_001.pdf (14.87 MB)
Synthesis of a 35-Member Stereoisomer Library of Bistramide A: Evaluation of Effects on actin State, Cell Cycle and Tumor Cell Growth
journal contributionposted on 2009-03-06, 00:00 authored by Iwona E. Wrona, Jason T. Lowe, Thomas J. Turbyville, Tanya R. Johnson, Julien Beignet, John A. Beutler, James S. Panek
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 γ-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.