5(B-1) 海綿Mycale izuensisから単離された新規HDAC阻害剤azumamides類の構造と活性(口頭発表の部)

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Histone deacetylases (HDACs) and histone acetyltransferases (HATs) regulate the acetylation of histones and are involved in the transcriptional activity of certain genes. HDAC inhibitors, such as tricostatin A and trapoxin A, are known to cause cell cycle arrest, differentiation or apoptosis of tumor cells, and a p53-independent induction of the cyclin dependent kinase inhibitor, p21. In addition to the effects on tumor, antiangiogenic effects by HDAC inhibitors are reported, recently. Therefore, HDAC inhibitors are expected as potential agents for the treatment of cancer. In our screening for HDAC inhibitors from Japanese marine invertebrates, we encountered the marine sponge Mycale izuensis. collected in the Amakusa Islands whose aqueous extract was highly active. Bioassay-guided fractionation led to the isolation of five active compounds, azumamides A-E. The molecular formula of azumamide A (1) was determined to be C_<27>H_<39>N_5O_5 on the basis of HR-FABMS and NMR data. Interpretation of 2D NMR spectra indicated that the structure of 1 was composed of Ala, Val, and Phe, as well as an unprecedented novel amino acid, 3-amino-2-methyl-5-nonenedioic acid 9-amide (Amnaa). The absolute stereochemistry of Ala, Val, and Phe was determined by Marfey analysis to be all D. Stereochemistry of Amnaa was determined as 2S, 3R by comparing ^1H NMR chemical shifts of the MTPA amide derivative with those of the model compounds. The structures of azumamides B-E (2-5) were also determined following the same procedure as in the case of 1. Azumamides A-E (1-5) inhibited HDAC with IC_50 values ranging 23-617 ng/mL. Furthermore, azumamide A showed inhibitory activity against HDAC expressed in K562 cells as well as cytostatic effects on WiDr (human colon cancer cell) and K562 (human leukemia cell) cells with IC_50 values of 5.8 and 4.5 mM, respectively.
天然有機化合物討論会の論文
2004-10-01

5(B-1) 海綿Mycale izuensisから単離された新規HDAC阻害剤azumamides類の構造と活性(口頭発表の部)

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