Synthesis and in vivo SAR study of indolin-2-one-based multi-targeted inhibitors as potential anticancer agents

被引：31

作者：

Zhang, Long ^{[1
]}

Zheng, Qingmei ^{[1
]}

Yang, Yingying ^{[1
]}

Zhou, Haojie ^{[1
]}

Gong, Xingjiang ^{[1
]}

Zhao, Shuyong ^{[1
]}

Fan, Chuanwen ^{[1
]}

机构：

[1] Qilu Pharmaceut Co Ltd, Shandong Prov Key Lab Small Mol Targeted Drugs, Jinan 250100, Shandong, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 82卷

关键词：

Indolin-2-one analogues; In-vivo SAR; VEGFR-2; PDGFR-beta; Multi-targeted inhibitors; TYROSINE KINASE INHIBITOR; ANTIPROLIFERATIVE EVALUATION; SUNITINIB MALATE; SU11248; VEGF; HYPOTHYROIDISM; DISCOVERY; THERAPY; DESIGN;

D O I：

10.1016/j.ejmech.2014.05.051

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of indolin-2-one analogues were designed and synthesized, and all of them exhibited excellent in vitro potency. The structure and in vivo activity or toxicity relationship (in-vivo SAR) investigation of indolin-2-one structural analogues was carried out. In vivo efficacy studies indicated that 3b significantly suppressed tumor growth in HT-29 and NCI-H460 xenografts without causing significant loss of body weight. Kinase assay showed that compound 3b effectively inhibited the VEGFR-2, VEGFR-3, FLT3, Ret and PDGFR-beta kinases, but had little effect on the VEGFR-1 kinase. Besides, 3b showed higher selectivity for VEGFR-2 compared with PDGFR-beta. On the basis of its selectivity and safety properties, 3b was identified as a drug candidate for the treatment of cancer. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

收藏

页码：139 / 151

页数：13

相关论文

共 37 条

[1]

[Anonymous], 2005, J CLIN ONCOL

[2] Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects [J].

Bello, Carlo L. ;

Sherman, Laurie ;

Zhou, Jihao ;

Verkh, Lev ;

Smeraglia, John ;

Mount, Janessa ;

Klamerus, Karen J. .

ANTI-CANCER DRUGS, 2006, 17 (03) :353-358

[3] Advanced gastrointestinal stromal tumor in Europe: a review of updated treatment recommendations [J].

Blay, Jean-Yves ;

Reichardt, Peter .

EXPERT REVIEW OF ANTICANCER THERAPY, 2009, 9 (06) :831-838

[4] Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1 [J].

Cassinelli, Giuliana ;

Lanzi, Cinzia ;

Petrangolini, Giovanna ;

Tortoreto, Monica ;

Pratesi, Graziella ;

Cuccuru, Giuditta ;

Laccabue, Diletta ;

Supino, Rosanna ;

Belluco, Sara ;

Favini, Enrica ;

Poletti, Anna ;

Zunino, Franco .

MOLECULAR CANCER THERAPEUTICS, 2006, 5 (09) :2388-2397

[5] The challenge of conducting pharmacoeconomic evaluations in oncology using crossover trials: The example of sunitinib for gastrointestinal stromal tumour [J].

Chabot, Isabelle ;

LeLorier, Jacques ;

Blackstein, Martin E. .

EUROPEAN JOURNAL OF CANCER, 2008, 44 (07) :972-977

[6] Coronary Microvascular Pericytes Are the Cellular Target of Sunitinib Malate-Induced Cardiotoxicity [J].

Chintalgattu, Vishnu ;

Rees, Meredith L. ;

Culver, James C. ;

Goel, Aditya ;

Jiffar, Tilahu ;

Zhang, Jianhu ;

Dunner, Kenneth, Jr. ;

Pati, Shibani ;

Bankson, James A. ;

Pasqualini, Renata ;

Arap, Wadih ;

Bryan, Nathan S. ;

Taegtmeyer, Heinrich ;

Langley, Robert R. ;

Yao, Hui ;

Kupferman, Michael E. ;

Entman, Mark L. ;

Dickinson, Mary E. ;

Khakoo, Aarif Y. .

SCIENCE TRANSLATIONAL MEDICINE, 2013, 5 (187)

[7] Sunitinib: From rational design to clinical efficacy [J].

Chow, Laura Q. M. ;

Eckhardt, S. Gail .

JOURNAL OF CLINICAL ONCOLOGY, 2007, 25 (07) :884-896

[8] Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib [J].

Chu, Tammy F. ;

Rupnick, Maria A. ;

Kerkela, Risto ;

Dallabrida, Susan M. ;

Zurakowski, David ;

Nguyen, Lisa ;

Woulfe, Kathleen ;

Pravda, Elke ;

Cassiola, Flavia ;

Desai, Jayesh ;

George, Suzanne ;

Morgan, Jeffrey A. ;

Harris, David M. ;

Ismail, Nesreen S. ;

Chen, Jey-Hsin ;

Schoen, Frederick J. ;

Van den Abbeele, Annick D. ;

Demetri, George D. ;

Force, Thomas ;

Chen, Ming Hui .

LANCET, 2007, 370 (9604) :2011-2019

[9] Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors [J].

Desai, Jayesh ;

Yassa, Leila ;

Marqusee, Ellen ;

George, Suzanne ;

Frates, Mary C. ;

Chen, Ming Hui ;

Morgan, Jeffrey A. ;

Dychter, Samuel S. ;

Larsen, P. Reed ;

Demetri, George D. ;

Alexander, Erik K. .

ANNALS OF INTERNAL MEDICINE, 2006, 145 (09) :660-664

[10] Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer [J].

Faivre, S ;

Delbaldo, C ;

Vera, K ;

Robert, C ;

Lozahic, S ;

Lassau, N ;

Bello, C ;

Deprimo, S ;

Brega, A ;

Massimini, G ;

Armand, JP ;

Scigalla, P ;

Raymond, E .

JOURNAL OF CLINICAL ONCOLOGY, 2006, 24 (01) :25-35

← 1 2 3 4 →