101(P45) 新規アポトーシス誘導物質cytotrienin類に関する研究(ポスター発表の部)

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In the course of screening for new antitumor secondary microbial metabolites, we have isolated four novel triene-ansamycins, cytotrienins A (1), B (2), C (3), and D (4), which possess a unique 1-amino-1-cyclopropane carboxylic acid moiety, from the fermentation broth of Streptomyces sp. isolated from a soil sample through a separation procedure guided by the apoptosis-inducing activity in vitro. Both 1 and 2 exhibited a potent apoptosis-inducing activity on HL-60 cells (a human promyelocytic leukemia cell line). Molecular formulas of 1, 2, 3, and 4 were determined to be C_<37>H_<48>N_2O_8, C_<37>H_<50>N_2O_8, C_<37>H_<46>N_2O_8, and C_<37>H_<48>N_2O_8 from HR-FABMS spectral data, respectively. Structures of 1, 2, 3, and 4 were elucidated on the basis of spectroscopic data, especially by detailed analyses of their _^1H and ^<13>C NMR spectra with aid of 2D NMR spectroscopy including FG-DQFCOSY, FG-HMQC, and FG-HMBC techniques as shown in Fig. 1 and Fig. 3. This is the first example in a series of triene-ansamycin antibiotics, demonstrating that the compounds involve a 1-amino-1-cyclopropane carboxylic acid unit, such as cytotrienins A(1)〜D(4). Cytotrienins are clearly different from the triene-ansamycin antibiotics possessing D-alanine such as mycotrienins at C-11. Compounds 1〜4 were considered to be a series of related biogenetic analogs of mycotrienins. It is interest in attempting to study the biosynthesis of 1〜4, especially for the 1-amino-1-cyclopropane carboxylic acid moiety. Both 1 and 2 induced apoptosis to HL-60 cells with ED_<50> values of 0.005μg/mL. The HL-60 cells treated with 0.01μg/mL of 1 for 16 hours contained the condensed chromatin and fragmentated nuclei as visualized by staining with Hoechst Dye 33258 (Fig. 4: A〜D). When HL-60 cells were treated with 0.01μ/mL of 1, agarose gel electrophoresis of DNA revealed a "ladder" pattern as shown in Fig. 4(E), indicating preferential DNA degradation at the internucleosomal cleavage of genomic DNA. These data suggest that cell death induced by 1 resulted a programmed cellular respone, apoptosis. Further studies on the biological studies of cytotrienins are in progress.
天然有機化合物討論会の論文
1997-07-20

101(P45) 新規アポトーシス誘導物質cytotrienin類に関する研究(ポスター発表の部)

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