Abstract
A compound that inhibits the formation of a complex composed of the ubiquitin E2 enzyme Ubc13 and Uev1A was isolated from the marine sponge Leucetta aff. microrhaphis. The compound was identified as leucettamol A (1) by spectroscopic analysis. Its inhibition of Ubc13-Uev1A interaction was tested by the ELISA method, revealing an IC(50) value of 50 microg/mL. The compound is the first inhibitor of Ubc13-Uev1A interaction, that is, that of the E2 activity of Ubc13. Such inhibitors are presumed to be leads for anti-cancer agents that upregulate activity of the tumor suppressor p53 protein. Interestingly, hydrogenation of 1 increased its inhibitory activity with an IC(50) value of 4 microg/mL, while its tetraacetate derivative was inactive, indicating that the hydroxy and/or amino groups of 1 are required for the inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Crystallography, X-Ray / methods
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Dimerization
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic*
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Genes, p53
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Porifera / drug effects
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Porifera / metabolism*
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Recombinant Proteins / chemistry
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Sphingolipids / chemical synthesis
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Sphingolipids / pharmacology*
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Transcription Factors / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / metabolism
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Ubiquitin-Conjugating Enzymes / antagonists & inhibitors*
Substances
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Antineoplastic Agents
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Recombinant Proteins
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Sphingolipids
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TP53 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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leucettamol A
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UBE2N protein, human
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UBE2V1 protein, human
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Ubiquitin-Conjugating Enzymes