Antitumor Agents. 211. Fluorinated 2-Phenyl-4-quinolone Derivatives as Antimitotic Antitumor Agents

Yi, Xin; Yang, Zhengyu; Xia, Peng; Hackl, Torben; Hamel, Ernest; Mauger, Anthony B.; Wu, Jing; Lee, Kuo‐Hsiung

doi:10.1021/jm0101085

Cited by 134 publications

(73 citation statements)

References 13 publications

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“…has undergone an activating phosphorylation (on Thr 161 ) by CAK, that inhibitory phosphorylation (on Thr 14 and Tyr 15 ) has been removed by active Cdc25C phosphatase, that Cdc2 associates with cyclin B1, and that complex translocates to the nucleus (24). In this study, CHM-1 arrested the growth of cancer cells at the G 2 -M phase and then induced apoptotic cell death.…”

Section: Discussionmentioning

confidence: 58%

CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo

Wang

Pan

Huang

et al. 2008

Molecular Cancer Therapeutics

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Hepatocellular carcinoma is highly chemoresistant to currently available chemotherapeutic agents. In this study, 2 ¶-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1), a synthetic 6,7-substituted 2-phenyl-4-quinolone, was identified as a potent and selective antitumor agent in human hepatocellular carcinoma. CHM-1 induced growth inhibition of HA22T, Hep3B, and HepG2 cells in a concentration-dependent manner but did not obviously impair the viability of normal cells at the IC 50 for liver cancer cells. CHM-1-induced apoptosis was also characterized by immunofluorescence microscopy. CHM-1 interacted with tubulin at the colchicine-binding site, markedly inhibited tubulin polymerization both in vitro and in vivo, and disrupted microtubule organization. CHM-1 caused cell cycle arrest at G 2 -M phase by activating Cdc2/cyclin B1 complex activity. CHM-1-induced cell death, activation of Cdc2 kinase activity, and elevation of MPM2 phosphoepitopes were profoundly attenuated by roscovitine, a specific cyclin-dependent kinase inhibitor. CHM-1 did not modulate the caspase cascade, and the pan-caspaseinhibitor z-VAD-fmk did not abolish CHM-1-induced cell death. However, CHM-1 induced the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. Small interfering RNA targeting of AIF substantially attenuated CHM-1-induced AIF translocation. Importantly, CHM-1 inhibited tumor growth and prolonged the lifespan in mice inoculated with HA22T cells. In conclusion, we show that CHM-1 exhibits a novel antimitotic antitumor activity against human hepatocellular carcinoma both in vitro and in vivo via a caspase-independent pathway. CHM-1 is a promising chemotherapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially hepatocellular carcinoma. [Mol Cancer Ther 2008;7(2):350 -60]

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Section: Discussionmentioning

confidence: 58%

CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo

Wang

Pan

Huang

et al. 2008

Molecular Cancer Therapeutics

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“…The 2-arylquinolin-4-ones and their quinoline derivatives continue to receive considerable attention in chemistry because of their wide range of pharmacological applications [1][2][3][4]. The 2-arylquinolin-4(1H)-one derivatives, for example, are known to exhibit antibacterial [1] and antitumour properties [2].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and further studies of chemical transformation of the 2-aryl-3-halogenoquinolin-4(1H)-one derivatives

Mphahlele

Nwamadi

Mabeta

2006

Journal of Heterocyclic Chemistry

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The C-3 brominated and iodinated derivatives were prepared from the corresponding 2-arylquinolin-4(1H)-ones and their NMe-4-oxo derivatives using pyridinium tribromide in acetic acid or iodine-Na 2 CO 3 mixture in THF. The results of further studies of chemical transformation of the prepared α-haloenones and preliminary antitumour activity of the 3-bromo NH-4-oxo and NMe-4-oxo derivatives are also described.

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“…The 2-phenyl-4-quinolones and related compounds, a series of synthetic quinolone derivatives, were found to inhibit tubulin polymerization and disrupt microtubule organization, and they act as antimitotic agents (17)(18)(19)(20)(21). It was reported that the 2-phenylpyrroloquinolin-4-ones have antitumor activity in vitro and in vivo (22).…”

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confidence: 99%

CHM-1, a New Vascular Targeting Agent, Induces Apoptosis of Human Umbilical Vein Endothelial Cells via p53-mediated Death Receptor 5 Up-regulation

Tsai

Pan

Sun

et al. 2010

Journal of Biological Chemistry

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CHM-1 (2-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone) has been identified as a potent antitumor agent in human hepatocellular carcinoma; however, its role in tumor angiogenesis is unclear. This study investigated the effects of CHM-1 and the mechanisms by which it exerts its antiangiogenic and vascular disrupting properties. Using a xenograft model antitumor assay, we found that CHM-1 significantly inhibits tumor growth and microvessel formation. Flow cytometry, immunofluorescence microscopy, and cell death enzyme-linked immunosorbent assay kit revealed that CHM-1 inhibits growth of human umbilical vein endothelial cells (HUVEC) by induction of apoptotic cell death in a concentration-dependent manner. CHM-1 also suppresses HUVEC migration and capillary-like tube formation. We were able to correlate CHM-1-induced apoptosis in HUVEC with the cleavage of procaspase-3, -7, and -8, as well as with the cleavage of poly(ADP-ribose) polymerase by Western blotting assay. Such sensitization was achieved through up-regulation of death receptor 5 (DR5) but not DR4 or Fas. CHM-1 was also capable of increasing the expression level of p53, and most importantly, the induction of DR5 by CHM-1 was abolished by p53 small interfering RNA. Taken together, the results of this study indicate that CHM-1 exhibits vascular targeting activity associated with the induction of DR5-mediated endothelial cell apoptosis through p53 up-regulation, which suggests its potential as an antivascular and antitumor therapeutic agent.In neoplasm, malignant angiogenesis and tumor mortality are highly associated with each other. Almost every step of aggressive tumor growth and metastatic dissemination relies on a functional vascular network to provide tumor cells with oxygen and nutrients and to remove waste products associated with tumor metabolism, a crucial hallmark of cancer (1). Nowadays, several antiangiogenic strategies have been developed to inhibit tumor growth and metastasis. In addition to the indirect interference of proangiogenic communication between the tumor and endothelial cell compartments, several recent reports have suggested that the induction of apoptosis in proliferation of endothelial cells may represent a potential therapeutic strategy in the treatment of neovascularization-related diseases (2-4). For instance, numerous natural angiogenic inhibitors, such as endostatin, angiostatin, and thrombospondin-1, act in part through selective triggering apoptosis in endothelial cells, resulting in vascular regression (5, 6). Several antitubulin-binding agents (e.g. CA-4-phosphate, ZD6126, and TZT-1027) and flavonoids (5,6-dimethylxanthenone-4-acetic acid) have demonstrated the ability to induce apoptosis of tumor vascular endothelial cells, leading to the rapid collapse and obstruction of tumor vessels and ultimately causing a tumor vascular shutdown effect (7).Apoptosis is an intracellular suicide program possessing morphologic characteristics and biochemical features, including chromatin condensation, nuclear DNA fragmentation, cell s...

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Antitumor Agents. 211. Fluorinated 2-Phenyl-4-quinolone Derivatives as Antimitotic Antitumor Agents

Cited by 134 publications

References 13 publications

CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo

CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo

Synthesis and further studies of chemical transformation of the 2-aryl-3-halogenoquinolin-4(1H)-one derivatives

CHM-1, a New Vascular Targeting Agent, Induces Apoptosis of Human Umbilical Vein Endothelial Cells via p53-mediated Death Receptor 5 Up-regulation

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