Screening Technologies Branch

Frederick, MD, United States

Screening Technologies Branch

Frederick, MD, United States
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Romagnoli R.,University of Ferrara | Baraldi P.G.,University of Ferrara | Cruz-Lopez O.,University of Ferrara | Cara C.L.,University of Ferrara | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

In a continuing study of hybrid compounds containing the α-bromoacryloyl moiety as potential anticancer drugs, we synthesized a novel series of hybrids 4a-h, in which this moiety was linked to a 1,5-diaryl-1,4-pentadien-3-one system. Many of the conjugates prepared (4b, 4c, 4e and 4g) demonstrated pronounced, submicromolar antiproliferative activity against four cancer cell lines. Moreover, compound 4b induced apoptosis through the mitochondrial pathway and activated caspase-3 in a concentration-dependent manner. © 2010 Elsevier Ltd. All rights reserved.

Lin Y.-C.,China Medical University at Taichung | Tsai J.-Y.,China Medical University at Taichung | Yang J.-S.,China Medical University at Taichung | Lee Y.-H.,China Medical University at Taichung | And 5 more authors.
International Journal of Oncology | Year: 2013

A novel synthetic compound 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2, 3-b]indole (HAC-Y6) demonstrated selective anticancer activity. In the present study, COLO 205 cells were treated with HAC-Y6 to investigate the molecular mechanisms underlying its effects. HAC-Y6 induced growth inhibition, G2/M arrest and apoptosis in COLO 205 cells with an IC50 of 0.52±0.035 μM. Annexin V/PI double staining demonstrated the presence of apoptotic cells. JC-1 staining analysis showed that HAC-Y6 decreased mitochondrial membrane potential in support of apoptosis. An immunostaining assay revealed that HAC-Y6 depolymerized microtubules. Treatment of COLO 205 cells with HAC-Y6 resulted in increased expression of BubR1 and cyclin B1 and decreased expression of aurora A, phospho-aurora A, aurora B, phospho-aurora B and phospho-H3. HAC-Y6 treatment increased protein levels of active caspase-3, caspase-9, Endo G, AIF, Apaf-1, cytochrome c and Bax, but treatment with the compound caused reduced levels of procaspase-3, procaspase-9, Bcl-xL and Bcl-2. Overall, our results suggest that HAC-Y6 exerts anticancer effects by disrupting microtubule assembly and inducing G2/M arrest, polyploidy and apoptosis via mitochondrial pathways in COLO 205 cells.

Andreani A.,University of Bologna | Burnelli S.,University of Bologna | Granaiola M.,University of Bologna | Leoni A.,University of Bologna | And 9 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

This paper reports the synthesis of new derivatives (formed by two indole systems separated by a central moiety) analogous of potent antitumor agents previously described. The activity of the bis-indoles bearing a pyridine core confirms the good result described in the previous paper and compound 4c was chosen for the first in vivo experiment (Hollow Fiber Assay). COMPARE analysis and structure-activity relationships were also considered. Contrary to data reported by other Authors, no correlations were found between antitumor activity and NQO1 induction. © 2010 Elsevier Ltd. All rights reserved.

Andreani A.,University of Bologna | Bellini S.,University of Bologna | Burnelli S.,University of Bologna | Granaiola M.,University of Bologna | And 11 more authors.
Journal of Medicinal Chemistry | Year: 2010

The synthesis of new substituted E-3-(3-indolylmethylene)-1,3-dihydroindol- 2-ones is reported. The antitumor activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. Structure-activity relationships are discussed. The action of selected compounds was investigated in MCF-7 breast cancer cells. The ability of these derivatives to inhibit cellular proliferation was accompanied by increased level of p53 and its transcriptional targets p21 and Bax, interference in the cell cycle progression with cell accumulation in the G2/M phase, and activation of apoptosis. © 2010 American Chemical Society.

Kozaka T.,University of North Carolina at Chapel Hill | Nakagawa-Goto K.,University of North Carolina at Chapel Hill | Shi Q.,University of North Carolina at Chapel Hill | Lai C.-Y.,University of North Carolina at Chapel Hill | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

As a part of our continuing study of colchicinoids as therapeutically useful antitumor drugs, thiocolchicine derivatives, including their phosphate and other water soluble salts, were synthesized and evaluated for inhibition of tubulin polymerization and for in vitro cytotoxicity. Three compounds, 7, 10, and 11, showed potent inhibition of tubulin assembly (IC 50 = 0.88-1.1 μM). In addition, compound 7, a water soluble succinic acid salt of N-deacetylthiocolchicine (4), showed potent cytotoxicity against a panel of tumor cell lines, suggesting it might be a potential lead to be developed as a therapeutic antitumor agent. Compound 8, a water soluble succinic acid salt of N,N-dimethyl-N-deacetylthiocolchicine (5), showed selective activities against HCT-8 and SK-BR-3 cells. N,N-Diethyl-N-deacetylthiocolchicine (6) seemed not to be a substrate for the P-gp efflux pump, based on the similar ED 50 values obtained against P-gp over-expressing KBvin (0.0146 μg/mL) cells and the parent KB (0.0200 μg/mL) cell line. © 2010 Elsevier Ltd. All rights reserved.

Mertins S.D.,Screening Technologies Branch
Anti-Cancer Drugs | Year: 2014

Evidence has accumulated that characterizes highly tumorigenic cancer cells residing in heterogeneous populations. The accepted term for such a subpopulation is cancer stem cells (CSCs). While many questions still remain about their precise role in the origin, progression, and drug resistance of tumors, it is clear they exist. In this review, a current understanding of the nature of CSC, their potential usefulness in prognosis, and the need to target them will be discussed. In particular, separate studies now suggest that the CSC is plastic in its phenotype, toggling between tumorigenic and nontumorigenic states depending on both intrinsic and extrinsic conditions. Because of this, a static view of gene and protein levels defined by correlations may not be sufficient to either predict disease progression or aid in the discovery and development of drugs to molecular targets leading to cures. Quantitative dynamic modeling, a bottom up systems biology approach whereby signal transduction pathways are described by differential equations, may offer a novel means to overcome the challenges of oncology today. In conclusion, the complexity of CSCs can be captured in mathematical models that may be useful for selecting molecular targets, defining drug action, and predicting sensitivity or resistance pathways for improved patient outcomes. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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