Synthesis of a 35-Member Stereoisomer Library of Bistramide A: Evaluation of Effects on actin State, Cell Cycle and Tumor Cell Growth

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, t...

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Bibliographic Details
Published in:Journal of organic chemistry 2009-03, Vol.74 (5), p.1897-1916
Main Authors: Wrona, Iwona E, Lowe, Jason T, Turbyville, Thomas J, Johnson, Tanya R, Beignet, Julien, Beutler, John A, Panek, James S
Format: Article
Language:English
Subjects:
Acetamides - chemical synthesis
Acetamides - chemistry
Acetamides - pharmacology
Actins - antagonists & inhibitors
Actins - chemistry
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Cycle - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Chemistry
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives
Humans
Models, Molecular
Molecular Conformation
Organic chemistry
Peptides
Preparations and properties
Pyrans - chemical synthesis
Pyrans - chemistry
Pyrans - pharmacology
Spiro Compounds - chemical synthesis
Spiro Compounds - chemistry
Spiro Compounds - pharmacology
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo802269q