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	Iwona E Wrona, Jason T Lowe, Thomas J Turbyville, Tanya R Johnson, Julien Beignet, John A Beutler, James S Panek
Journal	The Journal of organic chemistry (J Org Chem) Vol. 74 Issue 5 Pg. 1897-916 (Mar 06 2009) ISSN: 1520-6904 [Electronic] United States
PMID	19191575 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References	Acetamides Actins Antineoplastic Agents Pyrans Spiro Compounds bistratene A
Topics	Acetamides (chemical synthesis, chemistry, pharmacology) Actins (antagonists & inhibitors, chemistry) Antineoplastic Agents (chemical synthesis, chemistry, pharmacology) Cell Cycle (drug effects) Cell Line, Tumor Cell Proliferation (drug effects) Crystallography, X-Ray Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Humans Models, Molecular Molecular Conformation Pyrans (chemical synthesis, chemistry, pharmacology) Spiro Compounds (chemical synthesis, chemistry, pharmacology) Stereoisomerism Structure-Activity Relationship

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