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Mei-Jung Lai,
Han-Li Huang,
Shiow-Lin Pan,
Yi-Min Liu,
Chieh-Yu Peng,
Hsueh-Yun Lee,
Teng-Kuang Yeh,
Po-Hsien Huang,
Che-Ming Teng,
Ching-Shih Chen,
Hsun-Yueh Chuang,
Jing-Ping Liou
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ABSTRACT: A series of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indoles has been identified as a new class of histone deacetylase inhibitors. Compounds 8, 11, 12, 13, and 14 demonstrated stronger antiproliferative activities than 1 (SAHA) with GI(50) values ranging from 0.36 to 1.21 μM against Hep3B, MDA-MB-231, PC-3, and A549 human cancer cell lines. Lead compound 8 showed remarkable HDAC 1, 2, and 6 isoenzymes inhibitory activities with IC(50) values of 12.3, 4.0, 1.0 nM, respectively, which are comparable to 1. In in vivo efficacy evaluation against lung A549 xenograft model, 8 displayed better antitumor activity than compound 1.
Journal of Medicinal Chemistry 03/2012; 55(8):3777-91. · 4.80 Impact Factor
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PLoS ONE 01/2012; 7(9). · 4.09 Impact Factor
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ABSTRACT: Recently, histone deacetylase (HDAC) inhibitors have emerged as a promising class of drugs for treatment of cancers, especially subcutaneous T-cell lymphoma. In this study, we demonstrated that MPT0E028, a novel N-hydroxyacrylamide-derived HDAC inhibitor, inhibited human colorectal cancer HCT116 cell growth in vitro and in vivo. The results of NCI-60 screening showed that MPT0E028 inhibited proliferation in both solid and hematological tumor cell lines at micromolar concentrations, and was especially potent in HCT116 cells. MPT0E028 had a stronger apoptotic activity and inhibited HDACs activity more potently than SAHA, the first therapeutic HDAC inhibitor proved by FDA. In vivo murine model, the growth of HCT116 tumor xenograft was delayed and inhibited after treatment with MPT0E028 in a dose-dependent manner. Based on in vivo study, MPT0E028 showed stronger anti-cancer efficacy than SAHA. No significant body weight difference or other adverse effects were observed in both MPT0E028-and SAHA-treated groups. Taken together, our results demonstrate that MPT0E028 has several properties and is potential as a promising anti-cancer therapeutic drug.
PLoS ONE 01/2012; 7(8):e43645. · 4.09 Impact Factor
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Mei-Jung Lai,
Jang-Yang Chang,
Hsueh-Yun Lee,
Ching-Chuan Kuo,
Mei-Hsiang Lin,
Hsing-Pang Hsieh,
Chi-Yen Chang,
Jian-Sung Wu,
Su-Ying Wu,
Kuang-Shing Shey,
Jing-Ping Liou
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ABSTRACT: A novel series of the biheterocycles-based compounds with core structure distinguished from combretastatin A-4 (1) and colchicine (5) have been synthesized and evaluated as potent anti-mitotic agents. Compound 1-(4'-Indolyl and 6'-quinolinyl)-4,5,6-trimethoxyindoles 13 and 19 showed substantial anti-proliferative activity against various human cancer cell lines, regardless to the tissue origin and the expression of multiple-drug resistance MDR1, with a mean IC(50) value of 38 and 24 nM respectively. Compound 13 (IC(50) = 1.7 μM) also exhibited similar anti-tubulin activities to 1 (IC(50) = 1.8 μM) and displayed strong binding property to the colchicine binding site on the microtubules. Computational modeling analysis revealed that the binding mechanism of compound 13 is similar to that of CA4.
European journal of medicinal chemistry 05/2011; 46(9):3623-9. · 3.27 Impact Factor
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ABSTRACT: In an attempt to mimic the 3,4,5-trimethoxyphenyl-Z-stilbene moiety of combretastatin A-4, a series of N-aryl-5,6,7-trimethoxyindoles were synthesized via copper-catalyzed Ullmann-type N-arylation through the corresponding 5,6,7-trimethoxyindole and aryl halides. These synthesized compounds demonstrated potent antiproliferative activity providing a novel skeleton for potent tubulin polymerization inhibitors.
Organic & Biomolecular Chemistry 03/2011; 9(9):3154-7. · 3.70 Impact Factor
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ABSTRACT: A series of novel 2-amino-3,4,5-trimethoxybenzophenone analogues exhibited excellent activity as tubulin polymerization inhibitors by targeting the colchicine binding site of microtubules. The lead compound 17 exhibited an IC50 value of 1.6 μM, similar to that of combretastatin A-4 (IC50=1.9 μM). It also displayed remarkable anti-proliferative activity, with IC50 values ranging from 7-16 nM against a variety of human cancer cell lines and one MDR(+) cancer cell line. SAR information indicated that the introduction of an amino group at the C2 position of benzophenone ring A and the C3' position of benzophenone ring B play important roles in maximizing activity.
ChemMedChem 03/2011; 6(3):450-6. · 3.15 Impact Factor
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ABSTRACT: A series of 1-benzyl-4,5,6-trimethoxyindoles was designed and prepared as a novel class of potent antimitotic agents acting through the colchicine binding site of tubulin. Compounds 10 and 11 showed excellent antiproliferative activity with mean IC(50) values of 26 and 27 nM, respectively, in a diverse set of human cancer lines from different organs, including a MDR+ line. They also displayed substantial antitubulin efficacy with IC(50) values of 3.5 and 2.6 muM, respectively, representing an improvement over colchicine (IC(50)=4.3 muM).
ChemMedChem 04/2009; 4(4):588-93. · 3.15 Impact Factor
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ChemMedChem 03/2009; 4(4):588 - 593. · 3.15 Impact Factor
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Gadarla Randheer Reddy,
Ching-Chuan Kuo,
Uan-Kang Tan,
Mohane Selvaraj Coumar,
Chi-Yen Chang,
Yi-Kun Chiang, Mei-Jung Lai,
Jiann-Yih Yeh,
Su-Ying Wu,
Jang-Yang Chang,
Jing-Ping Liou,
Hsing-Pang Hsieh
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ABSTRACT: A series of aroylnaphthalene derivatives were prepared as bioisosteres of combrestatin A-4 and evaluated for anticancer activity. 2-Amino-1-aroylnaphthalene and 2-hydroxy-1-aroylnaphthalene, 9 and 8, respectively, showed strong antiproliferative activity with IC(50) values of 2.1-26.3 nM against a panel of human cancer cell lines including multiple-drug resistant cell line. Compound 9 demonstrated better antiproliferative activity and has a comparable tubulin binding efficacy as that of colchicine.
Journal of Medicinal Chemistry 12/2008; 51(24):8163-7. · 4.80 Impact Factor
