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ABSTRACT: Three, new, fully synthetic glycosylated isomalyngamide A analogs 4-6 were prepared and evaluated for their anti-migratory activities in human breast cancer cells. The results of the study show that two glycosylated derivatives 4 and 5, containing mannose and galactose appendages, suppress metastatic events (e.g., migration, invasion and adhesion) in human breast adenocarcinoma MDA-MB-231 cells at "nontoxic" concentration levels. In contrast, derivative 6 that contains a lactose moiety, displays a less potent activity. The findings show that monosaccharide rather than disaccharide appendages to the isomalyngamide A backbone more greatly influence cell migration and invasive ability. Evidence has been gained for a mechanism for inhibition of metastatic activities in MDA-MB-231 cells by 4 and 5, involving inactivation of the expression of p-FAK and paxillin through the integrin-mediated antimetastatic pathway.
European journal of medicinal chemistry 04/2013; 64C:169-178. · 3.27 Impact Factor
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ABSTRACT: Current chemical and biological interest in indole-3-carbinol (I3C) and its metabolites has resulted in the discovery of new biologically active indoles. As part of a program aimed at the development of indole analogues, tetraindoles 1-15 were prepared and their antiproliferative effects on human breast cancer cells were evaluated. The results show that the 5-hydroxy-tetraindole 8 (SK228) has optimum antiproliferative activity against breast adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity involves G(2)-phase arrest of the cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2. Further observations suggest that 5-hydroxy-tetraindole 8 induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. Given the fact that I3C and its metabolites have been shown to improve therapeutic efficacy and to have a broad range of antitumor activities in human cancer cells, the current findings have important pharmacological relevance as they open a promising route to the development of a potential chemotherapeutic application of tetraindoles as agents for the treatment of breast cancer.
Journal of Medicinal Chemistry 02/2012; 55(4):1583-92. · 4.80 Impact Factor
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ABSTRACT: Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub-micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase-3 and -9 without affecting caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F-actin cytoskeleton was disrupted after low-dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase-3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.
International Journal of Cancer 08/2011; 131(3):722-32. · 5.44 Impact Factor
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ABSTRACT: A series of polyfluorinated bipyridine cisplatins 2-6 were prepared, characterized, and evaluated for their in vitro cytotoxicities against a panel of human cancer cell lines, MCF7 (breast adenocarcinoma), MDA-MB-231 (breast adenocarcinoma) and A549 (lung adenocarcinoma). The results show that a correlation between the relative order of lipophilicity of complexes 2-4 and their cytotoxicity is established by following the trend: 4>2>3. Complex 4, which is the most active compound in the series, was found to be a more effective and selective anticancer agent than cisplatin. Complex 4 inhibited cancer cell proliferation by partial intercalation to DNA, which subsequently resulted in induction of S-G2/M arrest and apoptosis.
Bioorganic & medicinal chemistry 08/2011; 19(16):4887-94. · 2.82 Impact Factor
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ABSTRACT: Isomalyngamide A (1) and A-1 (2) were isolated from the Taiwanese Lyngbya majuscule and the latter structure was elucidated by a combination of NMR spectroscopic analysis and HRESIMS measurement. We report the isolation of isomalyngamide A (1), discovery of isomalyngamide A-1 (2) and their synthetic analogs (3-9), which are further demonstrated to have therapeutic potential against tumor cell migration at the level of nanomolar to micromolar ranges, perhaps, by inactivating the expression of p-FAK, FAK, p-Akt and Akt through β1 integrin-mediated antimetastatic pathway.
European journal of medicinal chemistry 05/2011; 46(9):3810-9. · 3.27 Impact Factor
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ABSTRACT: Aberrant sialylation catalyzed by sialyltransferases (STs) is frequently found in cancer cells and is associated with increased cancer metastasis. However, ST inhibitors developed till now are not applicable for clinical use because of their poor cell permeability. In this study, a novel ST inhibitor AL10 derived from the lead compound lithocholic acid identified in our previous study is synthesized and the anti-cancer effect of this compound is studied. AL10 is cell-permeable and effectively attenuates total sialylation on cell surface. This inhibitor shows no cytotoxicity but inhibits adhesion, migration, actin polymerization and invasion of alpha-2,3-ST-overexpressing A549 and CL1.5 human lung cells. Inhibition of adhesion and migration by AL10 is associated with reduced sialylation of various integrin molecules and attenuated activation of the integrin downstream signaling mediator focal adhesion kinase. More importantly, AL10 significantly suppresses experimental lung metastasis in vivo without affecting liver and kidney function of experimental animals as determined by serum biochemical assays. Taken together, AL10 is the first ST inhibitor, which exhibits potent anti-metastatic activity in vivo and may be useful for clinical cancer treatment.
Journal of Cellular Physiology 05/2010; 223(2):492-9. · 3.87 Impact Factor
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ABSTRACT: This study describes the synthesis and structure-activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.
Bioorganic & medicinal chemistry letters 12/2009; 20(3):1148-52. · 2.65 Impact Factor
