First Total Synthesis of (+/-)-6 '-Methoxyretrojusticidin B Using Regiocontrolled Benzannulation: Structural Inconsistency with Procumphthalide A and Its Revision to 5 '-Methoxyretrochinensin

We achieved the first total synthesis of a novel (+/-)-6'-methoxyretrojusticidin B, which was proposed as procumphthalide A, utilizing regiocontrolled benzannulation of an aryl(aryl')-2,2-dichlorocyclopropylmethanol as the key step. (1)H NMR spectral data suggested that the structure of the synthesized product, 6'-methoxyretrojusticidin B, was inconsistent with that of natural procumphthalide A. A computational study of the rotational barrier rationally supports the existence of a rigid chiral axis in 6'-methoxyretrojusticidin B. The revised structural elucidation of natural procumphthalide A was concluded to be 5'-methoxyretrochinensin.ArticleSYNLETT. 2010(15):2275-2278 (2010)journal articl

Combined mutation of Apc, Kras and Tgfbr2 effectively drives metastasis of intestinal cancer

13301甲第4656号博士（医学）金沢大学博士論文要旨Abstract 以下に掲載：Cancer Research 78(5) pp.1334-1346 2018. AACR. 共著者：Eri Sakai, Mizuho Nakayama, Hiroko Oshima, Yuta Kouyama, Atsushi Niida, Satoshi Fujii, Atsushi Ochiai, Keiichi I. Nakayama, Koshi Mimori, Yutaka Suzuki, Chang Pyo Hong, Chan-Young Ock, Seong-Jin Kim, Masanobu Oshim

Combined mutation of Apc, Kras and Tgfbr2 effectively drives metastasis of intestinal cancer

13301甲第4656号博士（医学）金沢大学博士論文本文Full 以下に掲載：Cancer Research 78(5) pp.1334-1346 2018. AACR. 共著者：Eri Sakai, Mizuho Nakayama, Hiroko Oshima, Yuta Kouyama, Atsushi Niida, Satoshi Fujii, Atsushi Ochiai, Keiichi I. Nakayama, Koshi Mimori, Yutaka Suzuki, Chang Pyo Hong, Chan-Young Ock, Seong-Jin Kim, Masanobu Oshim

Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma

A dynamic phenotypic change contributes to the metastatic progression and drug resistance in malignant melanoma. Nevertheless, mechanisms for a phenotypic change have remained to be addressed. Here, we show that Met receptor expression changes in a cell-autonomous manner and can distinguish phenotypical differences in growth, as well as in metastatic and drug-resistant characteristics. In metastatic melanoma, the cells are composed of Met-low and Met-high populations. Met-low populations have stem-like gene expression profiles, are resistant to chemotherapeutic agents, and have shown abundant angiogenesis and rapid tumor growth in subcutaneous inoculation. Met-high populations have a differentiated phenotype, are relatively resistant to B-RAF inhibitor, and are highly metastatic to the lungs. Met plays a definitive role in lung metastasis because the lung metastasis of Met-high cells requires Met, and treatment of mice with the Met-containing exosomes from Methigh cells facilitates lung metastasis by Met-low cells. Clonal cell fate analysis showed the hierarchical phenotypical changes from Met-low to Met-high populations. Met-low cells either showed self-renewal or changed into Met-high cells, whereas Met-high cells remained Met-high. Clonal transition from Met-low to Met-high cells accompanied changes in the gene expression profile, in tumor growth, and in metastasis that were similar to those in Met-high cells. These findings indicate that malignant melanoma has the ability to undergo phenotypic change by a cell-intrinsic/autonomous mechanism that can be characterized by Met expression

Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma

A dynamic phenotypic change contributes to the metastatic progression and drug resistance in malignant melanoma. Nevertheless, mechanisms for a phenotypic change have remained to be addressed. Here, we show that Met receptor expression changes in a cell-autonomous manner and can distinguish phenotypical differences in growth, as well as in metastatic and drug-resistant characteristics. In metastatic melanoma, the cells are composed of Met-low and Met-high populations. Met-low populations have stem-like gene expression profiles, are resistant to chemotherapeutic agents, and have shown abundant angiogenesis and rapid tumor growth in subcutaneous inoculation. Met-high populations have a differentiated phenotype, are relatively resistant to B-RAF inhibitor, and are highly metastatic to the lungs. Met plays a definitive role in lung metastasis because the lung metastasis of Met-high cells requires Met, and treatment of mice with the Met-containing exosomes from Met-high cells facilitates lung metastasis by Met-low cells. Clonal cell fate analysis showed the hierarchical phenotypical changes from Met-low to Met-high populations. Met-low cells either showed self-renewal or changed into Met-high cells, whereas Met-high cells remained Met-high. Clonal transition from Met-low to Met-high cells accompanied changes in the gene expression profile, in tumor growth, and in metastasis that were similar to those in Met-high cells. These findings indicate that malignant melanoma has the ability to undergo phenotypic change by a cell-intrinsic/autonomous mechanism that can be characterized by Met expression

Selective cytotoxicity of dihydroorotate dehydrogenase inhibitors to human cancer cells under hypoxia and nutrient-deprived conditions

Human dihydroorotate dehydrogenase (HsDHODH) is a key enzyme of pyrimidine de novo biosynthesis pathway. It is located on the mitochondrial inner membrane and contributes to the respiratory chain by shuttling electrons to the ubiquinone pool. We have discovered ascofuranone (1), a natural compound produced by Acremonium sclerotigenum, and its derivatives are a potent class of HsDHODH inhibitors. We conducted a structure–activity relationship study and have identified functional groups of 1 that are essential for the inhibition of HsDHODH enzymatic activity. Furthermore, the binding mode of 1 and its derivatives to HsDHODH was demonstrated by co-crystallographic analysis and we show that these inhibitors bind at the ubiquinone binding site. In addition, the cytotoxicities of 1 and its potent derivatives 7, 8, and 9were studied using human cultured cancer cells. Interestingly, they showed selective and strong cytotoxicity to cancer cells cultured under microenvironment (hypoxia and nutrient-deprived) conditions. The selectivity ratio of 8 under this microenvironment show the most potent inhibition which was over 1000-fold higher compared to that under normal culture condition. Our studies suggest that under microenvironment conditions, cancer cells heavily depend on the pyrimidine de novo biosynthesis pathway. We also provide the first evidence that 1 and its derivatives are potential lead candidates for drug development which target the HsDHODH of cancer cells living under a tumor microenvironment

α-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells

α-Lipoic acid (α-LA), a naturally occurring anti-oxidant and co-factor for metabolic enzymes, suppresses the growth of different types of tumor cells. The mechanisms that are responsible for these results, however, remain to be elucidated. In the present study, we investigated the effects of α-LA on the proliferation and activation status of definitive receptor tyrosine kinases, epidermal growth factor receptor (EGFR) and Met/hepatocyte growth factor (HGF) receptor, in gefitinib-sensitive human non-small cell lung cancer cells harboring EGFRs with an activating mutation. The enantiomers R-α-LA and S-α-LA suppressed cell proliferation and increased the level of reactive oxygen species in HCC-827 and PC-9 human non-small cell lung cancer cells in an indistinguishable dose-dependent fashion. A phospho-receptor tyrosine kinase array and cell cycle analysis indicated that α-LA decreased tyrosine phosphorylation levels of EGFR, ErbB2, and Met, and this was associated with an inhibition in the cell-cycle transition from the G1 phase to the S phase without inducing apoptosis. Gefitinib, an inhibitor for EGFR tyrosine kinase, inhibited EGFR tyrosine phosphorylation/activation and proliferation of the cells. Instead, the addition of HGF induced Met tyrosine phosphorylation, and this was associated with a resistance to gefitinib-induced growth inhibition, which meant a gain in proliferative ability. In the presence of gefitinib and HGF, the addition of α-LA suppressed Met tyrosine phosphorylation, and this was associated with an inhibition in cell growth. These results suggest that the suppression of tyrosine phosphorylation/activation of growth factor receptors that is critical for the proliferation of human non-small cell lung cancer cells is a mechanism by which α-LA exerts growth inhibition for cancer cells. © 2013 Elsevier Ireland Ltd. All rights reserved

A combination of a DNA-chimera siRNA against PLK-1 and zoledronic acid suppresses the growth of malignant mesothelioma cells in vitro.

Although novel agents effective against malignant mesothelioma (MM) have been developed, the prognosis of patients with MM is still poor. We generated a DNA-chimeric siRNA against polo-like kinase-1 (PLK-1), which was more stable in human serum than the non-chimeric siRNA. The chimeric PLK-1 siRNA inhibited MM cell proliferation through the induction of apoptosis. Next, we investigated the effects of zoledronic acid (ZOL) on MM cells, and found that ZOL also induced apoptosis in MM cells. Furthermore, ZOL augmented the inhibitory effects of the PLK-1 siRNA. In conclusion, combining a PLK-1 siRNA with ZOL treatment is an attractive strategy against MM

Correlation of superconductivity with crystal structure in (NH3)(y)CsxFeSe

The superconducting transition temperature T-c of ammoniated metal-doped FeSe (NH3)(y)MxFeSe (M: metal atom) has been scaled with the FeSe plane spacing, and it has been suggested that the FeSe plane spacing depends on the location of metal atoms in (NH3)(y)MxFeSe crystals. Although the crystal structure of (NH3)(y)LixFeSe exhibiting a high T-c (similar to 44 K) was determined from neutron diffraction, the structure of (NH3)(y)MxFeSe exhibiting a low T-c (similar to 32 K) has not been determined thus far. Here, we determined the crystal structure of (NH3)(y)Cs0.4FeSe (T-c = 33 K) through the Rietveld refinement of the x-ray diffraction (XRD) pattern measured with synchrotron radiation at 30 K. The XRD pattern was analyzed based on two different models, on-center and off-center, under a space group of 14/mmm. In the on-center structure, the Cs occupies the 2a site and the N of NH3 may occupy either the 4c or 2b site, or both. In the off-center structure, the Cs may occupy either the 4c or 2b site, or both, while the N occupies the 2a site. Only an on-center structure model in which the Cs occupies the 2a and the N of NH3 occupies the 4c site provided reasonable results in the Rietveld analysis. Consequently, we concluded that (NH3)(y)Cs0.4FeSe can be assigned to the on-center structure, which produces a smaller FeSe plane spacing leading to the lower T-c