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Erica N. Parker Samuel O. Odutola Yifan Wang Tracy E. Strecker Rajeswari Mukherjee Zhe Shi David J. Chaplin Mary Lynn Trawick Kevin G. Pinney 《Bioorganic & medicinal chemistry letters》2017,27(5):1304-1310
The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202 nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50 = 189 nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94. 相似文献
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Rho-associated serine/threonine kinases (ROCKs) are principal regulators of the actin cytoskeleton that regulate the contractility, shape, motility, and invasion of cells. We explored the relationships between structure and anti-ROCK2 activity in a group of purine derivatives substituted at the C6 atom by piperidin-1-yl or azepan-1-yl groups. Structure-activity relationship (SAR) analyses suggested that anti-ROCK activity is retained, and may be further increased, by substitution of the parent compounds at the C2 atom or by expansion of the C6 side chain. These inhibitors of ROCK can reach effective concentrations within cells, as demonstrated by a decrease in phosphorylation of the ROCK target MLC, and by inhibition of the ROCK-dependent invasion of melanoma cells in the collagen matrix. Our study may be useful for further optimization of C6-substituted purine inhibitors of ROCKs and of other sensitive kinases identified by the screening of a broad panel of protein kinases. 相似文献
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Drug resistance and cancer cells metastasis have been the leading causes of chemotherapy failure and cancer-associated death in breast cancer patients. In present, various active molecules either exhibiting novel mechanism of action such as inducing autophagy or inhibiting metastasis have been developed to address these problems. However, the compounds exhibiting such dual functions have rarely been described. Previous work in our group showed that TSA, as a synthetic analog of asperphenamate, induced autophagic cell death in breast cancer cells instead of apoptosis. Furthermore, the target enzyme of TSA was predicted to be cathepin L (Cat L) by natural product consensus pharmacophore strategy. Accumulated evidences have shown that cathepsins are closely associated with migration and invasion of breast cancer cells. It seemed likely that TSA-like molecules may possess the dual functions of inducing autophagy and inhibiting metastasis. Therefore, sixty optically active derivatives were firstly designed and synthesized by replacing the A-ring moiety of TSA with other substituted-phenyl sulfonyl groups. Further cathepsin inhibitory activity assay showed that (S, S) and (S, R) isomers displayed no activity against four kinds of cathepsins (L, S, K, B), while all derivatives tested were inactive toward K and B subtypes. Compound 6a with meta-bromo substituent displayed the greatest inhibitory activity, and its inhibitory capability against Cat L and S was 3.9 and 11.5-fold more potent than that of TSA, respectively. Molecular docking also exhibited that 6a formed more hydrogen bonds or π-π contacts with Cat L or S than TSA. In order to determine whether 6a could play dual roles, its anti-cancer mechanism was further investigated. On the one hand, MDC staining experiment and western blotting analysis validated that 6a can induce autophagy in MDA-MB-231 cells. On the other hand, its metastatic inhibitory ability was also confirmed by wound healing and transwell chamber experiment. 相似文献
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Jiang YL Tang LQ Miyanaga S Igarashi Y Saiki I Liu ZP 《Bioorganic & medicinal chemistry letters》2011,21(4):1089-1091
Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to explore the preliminary structure-activity relationship and obtain more potent inhibitors, a series of brartemicin analogs were synthesized through the Mitsunobu coupling of the secondary hydroxyls benzyl protected α,α-d-trehalose with benzoic acid derivatives, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells in vitro. Among the synthetic analogs tested, 6,6′-bis(2,3-dimethoxybenzoyl)-α,α-d-trehalose (5e) was found to be the most potent anti-invasive agent, exhibited a 2.6-fold improvement with regard to the parent natural product brartemicin, and it is considered to be a promising lead molecule for the anti-metastasis. 相似文献
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Tanimura S Kadomoto R Tanaka T Zhang YJ Kouno I Kohno M 《Biochemical and biophysical research communications》2005,330(4):1306-1313
Elevated expression of matrix metalloproteinases (MMPs), especially that of MMP-2 and MMP-9, is associated with increased metastatic potential in many tumor cells. Recently, green tea polyphenol epigallocatechin-3-O-gallate (EGCG) has been shown to inhibit the MMP-2/-9 activity as well as the invasiveness of tumor cells. In this study, we have examined the inhibitory effect of hydrolyzable tannins (plant polyphenols) on the tumor cell invasion. Our results demonstrate that beta-d-glucose whose hydroxy groups are substituted entirely with galloyl group and further some of them are cross-linked to form hexahydroxydiphenoyl group, for example, suppresses the invasiveness of tumor cells much more potently than EGCG via direct inhibition of the MMP-2/-9 activity. Among those examined, 1,2,4-tri-O-galloyl-3,6-hexahydroxydiphenoyl-beta-d-glucose (punicafolin) inhibits the invasion of HT1080 fibrosarcoma cells most potently. These hydrolyzable tannins would provide new leads for the development of potent inhibitors against tumor metastasis. 相似文献
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Benjamin J. Buckley Hiwa Majed Ashraf Aboelela Elahe Minaei Longguang Jiang Karen Fildes Chen-Yi Cheung Darren Johnson Daniel Bachovchin Gregory M. Cook Mingdong Huang Marie Ranson Michael J. Kelso 《Bioorganic & medicinal chemistry letters》2019,29(24):126753
The oral K+-sparing diuretic amiloride shows anti-cancer side-activities in multiple rodent models. These effects appear to arise, at least in part, through moderate inhibition of the urokinase-type plasminogen activator (uPA, Ki = 2.4 µM), a pro-metastatic trypsin-like serine protease that is upregulated in many aggressive solid malignancies. In applying the selective optimization of side-activity (SOSA) approach, a focused library of twenty two 6-substituted amiloride derivatives were prepared, with multiple examples displaying uPA inhibitory potencies in the nM range. X-ray co-crystal structures revealed that the potency increases relative to amiloride arise from increased occupancy of uPA’s S1β subsite by the appended 6-substituents. Leading compounds were shown to have high selectivity over related trypsin-like serine proteases and no diuretic or anti-kaliuretic effects in rats. Compound 15 showed anti-metastatic effects in a xenografted mouse model of late-stage lung metastasis. 相似文献
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Specific blockade of the ERK pathway inhibits the invasiveness of tumor cells: down-regulation of matrix metalloproteinase-3/-9/-14 and CD44 总被引:8,自引:0,他引:8
Tanimura S Asato K Fujishiro SH Kohno M 《Biochemical and biophysical research communications》2003,304(4):801-806
Elevated expression of matrix metalloproteinases (MMPs) is associated with increased metastatic potential in many tumor cells. As activation of the ERK pathway has been linked to the expression of MMP-9, we examined a possible correlation between ERK activation, MMP-9 expression, and invasive phenotype in human tumor cells. Activation state of the ERK pathway in tumor cells was well correlated with the invasive phenotype, which was determined by the ability of cells to invade through reconstituted extracellular matrix. Elevated expression of MMP-9 as well as of MMP-3, MMP-14, and CD44 was observed in tumor cells in which constitutive activation of the ERK pathway is detected. Blockade of the ERK pathway by treatment with PD184352, a specific and powerful inhibitor of mitogen-activated protein (MAP) kinase/ERK kinase (MEK), suppressed the expression of MMP-3, MMP-9, MMP-14, and CD44, and inhibited markedly the invasiveness of tumor cells. These results imply that, in addition to anti-proliferative effects, specific blockade of the ERK pathway is expected to result in anti-metastatic effects in tumor cells. 相似文献
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