Concise syntheses of N-aryl-5,6,7-trimethoxyindoles as antimitotic and vascular disrupting agents: application of the copper-mediated Ullmann-type arylation

Lee, Hsueh Yun; Chang, Jang Yang; Chang, Ling-Yin; Lai, Wen Yang; Lai, Mei Jung; Shih, Kuang Hsing; Kuo, Ching Chuan; Chang, Chin-Chih; Liou, Jing Ping

doi:10.1039/c0ob01038c

Cited by 20 publications

(9 citation statements)

References 28 publications

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“…Compilation of indole-based inhibitors of tubulin assembly ( 6 , von Angerer, 1998; 7 and 8 , Pinney, 2001; 9 , Mahboobi and Beckers, 2001; 10 , Silvestri, 2004; 11 , Lee and Hsieh, 2004; 12 , Chang, 2007; 13 , Cachet, 2008; 14 and 15 , Chang, 2008; 16 , Romagnoli, 2008; 17 , Silvestri, 2011; 18 , Liou, 2011).…”

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confidence: 99%

Synthesis of a 2-Aryl-3-aroyl Indole Salt (OXi8007) Resembling Combretastatin A-4 with Application as a Vascular Disrupting Agent

et al. 2013

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The natural products colchicine and combretastatin A-4 (CA4) are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of a 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI50 = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC50 = 1.1 µM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent (VDA) that may prove useful for the treatment of cancer.

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confidence: 99%

Synthesis of a 2-Aryl-3-aroyl Indole Salt (OXi8007) Resembling Combretastatin A-4 with Application as a Vascular Disrupting Agent

et al. 2013

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“…Quinoline scaffold holds a distinguished role among heterocyclic compounds. For example, 5‐halogenated‐8‐aminoquinolines are important building blocks in synthesis of numerous medicinal compounds as potential anticancer, antimitotic, and antimalarial agents, as well as enzyme inhibitors and bioactive molecules . Therefore, functionalization of quinolines has gained considerable attention .…”

Section: Introductionmentioning

confidence: 99%

Copper(II)‐Catalyzed and Chelation‐Induced Remote C‐H Halogenation of Quinolines under Neutral Conditions

et al. 2017

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Copper(II)‐catalyzed highly regioselective halogenation of 8‐acylaminoquinolines was reported in this study. The halogenation of 8‐acylaminoquinolines proceeded smoothly in the presence of copper halide (CuBr2 or CuCl2) and potassium halide (KBr or KCl) as the catalyst and the halogen source, respectively, using oxygen in air as the terminal oxidant under neutral conditions to produce the corresponding C‐5 position halogenated products in satisfactory to good yields.

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“…The replacement of the trimethoxybenzene ring by benzoheterocyclic structures has received little attention so far . Recently, some trimethoxyindole derivatives have been reported as potent antimitotic agents with antivascular activity . To discover potential antitumor agents with a high degree of antivascular selectivity, following the SAR-guided discovery process, we replaced the trimethoxybenzene moiety with a more hindered trimethoxyindole skeleton, and synthesizing series of 5,6,7-trimethoxyindole derivatives: (1) 1-aroylindoles and 1-benzylindoles, (2) 3-aroylindoles and 3-benzylindoles, and (3) N1-substituted-3-aroylindoles and N1-substituted-3-benzylindoles.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure–Activity Relationships of N-Methyl-5,6,7-trimethoxylindoles as Novel Antimitotic and Vascular Disrupting Agents

Zhao

Chen

et al. 2013

J. Med. Chem.

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Several new series of 5,6,7-trimethoxyindole derivatives were synthesized and their structure-activity relationships (SARs) were studied. Some of these compounds exhibited strong antiproliferative activities in the submicromolar range. N-Methyl-5,6,7-trimethoxylindoles 21 and 31 displayed the highest antiproliferative activities, with IC50 values ranging from 22 to 125 nM in four human cancer cell lines and activated human umbilical vein endothelial cells (HUVECs). In addition to vascular disrupting activity verified by in vitro assays, compounds 21 and 31 displayed much higher selectivity for activated HUVECs versus quiescent HUVECs than those of colchicine and combretastatinA-4. The polymerization of cancer cell tubulin was inhibited and the cell cycle was arrested in the G2/M phase after treatment with 21 and 31. It was showed that 21 disrupted tumor vasculature by use of in vivo assay. Our results suggest that these two new compounds we synthesized may become the promising leads for the development of vascular disrupting agents.

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Concise syntheses of N-aryl-5,6,7-trimethoxyindoles as antimitotic and vascular disrupting agents: application of the copper-mediated Ullmann-type arylation

Cited by 20 publications

References 28 publications

Synthesis of a 2-Aryl-3-aroyl Indole Salt (OXi8007) Resembling Combretastatin A-4 with Application as a Vascular Disrupting Agent

Synthesis of a 2-Aryl-3-aroyl Indole Salt (OXi8007) Resembling Combretastatin A-4 with Application as a Vascular Disrupting Agent

Copper(II)‐Catalyzed and Chelation‐Induced Remote C‐H Halogenation of Quinolines under Neutral Conditions

Synthesis and Structure–Activity Relationships of N-Methyl-5,6,7-trimethoxylindoles as Novel Antimitotic and Vascular Disrupting Agents

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