Leucettamol A: a new inhibitor of Ubc13-Uev1A interaction isolated from a marine sponge, Leucetta aff. microrhaphis.
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.
Tsukamoto
Sachiko
S
Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. sachiko@faculty.chiba-u.jp
Takeuchi
Tomoharu
T
Rotinsulu
Henki
H
Mangindaan
Remy E P
RE
van Soest
Rob W M
RW
Ukai
Kazuyo
K
Kobayashi
Hisayoshi
H
Namikoshi
Michio
M
Ohta
Tomihisa
T
Yokosawa
Hideyoshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D011161:Porifera / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D013107:Sphingolipids / Q000138:chemical synthesis / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D013107:Sphingolipids; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C540199:leucettamol A; C471607:UBE2N protein, human; C471624:UBE2V1 protein, human; D044763:Ubiquitin-Conjugating Enzymes