Leucinostatin Y, a new peptaibiotic,
was isolated from the culture
broth of the entomoparasitic fungus Purpureocillium lilacinum 40-H-28. The planar structure was elucidated by detailed analysis
of its NMR and MS/MS data. The absolute configurations of the amino
acids were partially determined by an advanced Marfey’s method.
The biological activities of leucinostatin Y were assessed using human
pancreatic cancer cells, revealing the importance of the C-terminus
of leucinostatins for preferential cytotoxicity to cancer cells under
glucose-deprived conditions and inhibition of mitochondrial function.
Proteasome inhibitors are useful in the treatment of cancer. Recently, we found a new proteasome inhibitor, TP-110, derived from tyropeptin A produced by Kitasatospora sp. Here we report that TP-110 induces apoptosis in human prostate cancer PC-3 cells. TP-110 showed strong cytotoxicity to PC-3 cells (IC(50)=0.05 muM). It increased the number of cells in the G(2)-M phase and increased the accumulated amounts of the p21 and p27 proteins, which are negative regulators of cell cycle progression. Furthermore, it induced apoptosis along with chromatin condensation and DNA fragmentation in PC-3 cells, and TP-110-induced apoptosis appeared to be associated with caspase activation. Additionally, TP-110 inhibited not only the degradation of IkappaB and the nuclear translocation of nuclear factor-kappaB (NF-kappaB), but also the DNA binding activity of NF-kappaB. These results indicate that TP-110 shows a strong growth inhibition and apoptosis in PC-3 cells.
In the course of screening for substances that modulate immuneresponses in conjunction with T cell functions, we found conagenin, a novel, low MWimmunomodulator, in fermentation broths of Streptomyces roseosporus MI696-AF3. The structure of conagenin was determined to be (25)iY-[(2/?,35,4^)2,4-dihydroxy-3-methylpentanoyl]-2-methylserine on the basis of spectroscopic evidence (Fig. 1). In this paper, we report production and purification of conagenin, and its
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