Abstract
The synthesis and biological evaluation of three tubulysin analogs provides the first structure-activity relationship in this family of potent cytotoxic myxobacteria metabolites. Most importantly, the labile N,O-acetal at N(14) is not essential for biological activity. Further, structural simplifications are possible without abolishing biological activities. The N-terminal amino acid can be replaced with N-methylsarcosine, and the configuration at the acetoxy-bearing stereocenter at C(11) is important but not critical for almost all aspects of the biological profile. Our data encourage further development of these compounds as potential therapeutic agents in cancer treatment.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cattle
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Cell Line, Tumor
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Depsipeptides / metabolism
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Glioblastoma / drug therapy
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HeLa Cells
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Humans
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Mitosis / drug effects
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Oligopeptides / chemical synthesis
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Oligopeptides / chemistry*
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Oligopeptides / pharmacology
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Oligopeptides / therapeutic use
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / chemistry
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Thiazoles / therapeutic use
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Tubulin / drug effects
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Tubulin Modulators / pharmacology
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Vinblastine / metabolism
Substances
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4-(2-(6-sec-butyl-9-isopropyl-2,8-dimethyl-4,7,13-trioxo-12-oxa-2,5,8-triazatetradecan-11-yl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoic acid
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Depsipeptides
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N14-desacetoxytubulysin H
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Oligopeptides
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Thiazoles
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Tubulin
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Tubulin Modulators
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tubulysin A
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Vinblastine
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dolastatin 10