- Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives
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The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I–III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50 value of 1.8 ± 0.8 μM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.
- Yu, Zutao,Chen, Zhuo,Su, Qiongli,Ye, Shiqi,Yuan, Hongbo,Kuai, Mengni,Lv, Meng,Tu, Zhijun,Yang, Xiaoping,Liu, RangRu,Hu, Gaoyun,Li, Qianbin
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- Disubstituted indol-2(1H)-one derivative and preparation method and application thereof
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The invention discloses a disubstituted indol-2(1H)-one derivative and a preparation method and application thereof. The chemical structural formula of the disubstituted indol-2(1H)-one derivative is shown in the description. The derivative can be applied to preparation of antitumor medicine.
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- Novel synthesis of benzofuran- and indol-2-yl-methanamine derivatives
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We report on a novel synthesis towards benzofuran-2-yl-methanamine and indol-2-yl-methanamine derivatives by using ortho-methoxy and ortho-nitro substituted phenylacetic acids as starting material, respectively. For each compound series, a key intermediate bearing the oxazole-4-carboxylic acid methylester moiety was produced. Refluxing the ortho-methoxy series in HBr/HAc produced the desired benzofuran-2-yl-methanamines. Accordingly, for the synthesis of indoles the nitro-group was first reduced and refluxing these intermediates in HCl gave the corresponding indol-2-yl-methanamines. The method worked well with electron donating substituents. Limitations regarding electron withdrawing substituents are discussed. This straightforward synthetic procedure can be a useful approach to generate a variety of substituted benzofuran-2-yl-methanamine and indol-2-yl-methanamine compounds by starting from readily available phenylacetic acid derivatives.
- Schlosser, Joachim,Johannes, Eugen,Zindler, Melanie,Lemmerhirt, Jan,Sommer, Benjamin,Schütt, Martin,Peifer, Christian
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- Synthesis and biological evaluation of 3-ethylidene-1,3-dihydro-indol-2- ones as novel checkpoint 1 inhibitors
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Chk1 inhibitors have emerged as a novel class of neoplastic agents for abrogating the G2 DNA damage checkpoint arrest. Analogs of the Chk1 inhibitor, 3-ethylidene-1,3-dihydro-indol-2-one, were synthesized and tested in vitro for their inhibitory activitie
- Lin, Nan-Horng,Xia, Ping,Kovar, Peter,Park, Chang,Chen, Zehan,Zhang, Haiying,Rosenberg, Saul H.,Sham, Hing L.
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p. 421 - 426
(2007/10/03)
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- On the Synthesis of Tiliacora Alkaloids, II: Synthesis of the Asymmetrical Biphenyl Derivative
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The biphenyl derivatives S-1 and S-3 were obtained by mixed Ullmann reaction of the phenylacetic esters 3, 4 and 5.Because they contain selectively removable protective groups for the carboxyl functions, S-1 and S-3 are proper intermediates for the constitution selective reaction with the former described asymmetrical dibenzo-1,4-dioxin derivative K.
- Pachaly, Peter,Schaefer, Michael
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p. 483 - 487
(2007/10/02)
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