Biphenyl derivatives incorporating urea unit as novel VEGFR-2 inhibitors: Design, synthesis and biological evaluation

被引：54

作者：

Wang, Chen ^{[1
]}

Gao, Hongping ^{[1
]}

Dong, Jinyun ^{[1
]}

Zhang, Yanmin ^{[1
]}

Su, Ping ^{[1
]}

Shi, Yaling ^{[1
]}

Zhang, Jie ^{[1
]}

机构：

[1] Xi An Jiao Tong Univ, Sch Med, Xian 710061, Shaanxi Provinc, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 01期

关键词：

Angiogenesis; VEGFR-2; inhibitor; Biphenyl scaffold; Urea moiety; CANCER; ANGIOGENESIS; GROWTH; POTENT;

D O I：

10.1016/j.bmc.2013.11.027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of novel biphenyl urea derivates were synthesized and investigated for their potential to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2). In particular, A7, B3 and B4 displayed significant enzymatic inhibitory activities, with IC50 values of 4.06, 4.55 and 5.26 nM. Compound A7 exhibited potent antiproliferative activity on several cell lines. SAR study suggested that the introduction of methyl at ortho-position of the biphenyl urea and tertiary amine moiety could improve VEGFR-2 inhibitory activity and antitumor effects. Molecular docking indicated that the urea moiety formed four hydrogen bonds with DFG residue. These biphenyl ureas could serve as promising lead compounds for further optimization. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：277 / 284

页数：8

共 24 条

[1] Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor [J].

Albert, DH ;

Tapang, P ;

Magoc, TJ ;

Pease, LJ ;

Reuter, DR ;

Wei, RQ ;

Li, JL ;

Guo, J ;

Bousquet, PF ;

Ghoreishi-Haack, NS ;

Wang, B ;

Bukofzer, GT ;

Wang, YC ;

Stavropoulos, JA ;

Hartandi, K ;

Niquette, AL ;

Soni, N ;

Johnson, EF ;

McCall, JO ;

Bouska, JJ ;

Luo, Y ;

Donawho, CK ;

Dai, YJ ;

Marcotte, PA ;

Glaser, KB ;

Michaelides, MR ;

Davidsen, SK .

MOLECULAR CANCER THERAPEUTICS, 2006, 5 (04) :995-1006

[2] SEQUENTIAL DIRECTED ORTHO METALATION BORONIC ACID CROSS-COUPLING REACTIONS - A GENERAL REGIOSPECIFIC ROUTE TO OXYGENATED DIBENZO[B,D]PYRAN-6-ONES RELATED TO ELLAGIC ACID [J].

ALO, BI ;

KANDIL, A ;

PATIL, PA ;

SHARP, MJ ;

SIDDIQUI, MA ;

SNIECKUS, V ;

JOSEPHY, PD .

JOURNAL OF ORGANIC CHEMISTRY, 1991, 56 (12) :3763-3768

[3] Novel C-3N-urea, amide, and carbamate dihydroindazolo[5,4-a] pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors [J].

Becknell, Nadine C. ;

Zulli, Allison L. ;

Angeles, Thelma S. ;

Yang, Shi ;

Albom, Mark S. ;

Aimone, Lisa D. ;

Robinson, Candy ;

Chang, Hong ;

Hudkins, Robert L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (20) :5368-5372

[4]

Bertolini F., 2006, NAT REV DRUG DISCOV, V5, P835

[5] Angiogenesis in cancer and other diseases [J].

Carmeliet, P ;

Jain, RK .

NATURE, 2000, 407 (6801) :249-257

[6] Isoindolinone ureas: a novel class of KDR kinase inhibitors [J].

Curtin, ML ;

Frey, RR ;

Heyman, HR ;

Sarris, KA ;

Steinman, DH ;

Holmes, JH ;

Bousquet, PF ;

Cunha, GA ;

Moskey, MD ;

Ahmed, AA ;

Pease, LJ ;

Glaser, KB ;

Stewart, KD ;

Davidsen, SK ;

Michaelides, MR .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (17) :4505-4509

[7] Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: Synthesis, SAR, and in vivo anti-inflammatory activity [J].

DiMauro, Erin F. ;

Newcomb, John ;

Nunes, Joseph J. ;

Bemis, Jean E. ;

Boucher, Christina ;

Buchanan, John L. ;

Buckner, William H. ;

Cee, Victor J. ;

Chai, Lilly ;

Deak, Holly L. ;

Epstein, Linda F. ;

Faust, Ted ;

Gallant, Paul ;

Geuns-Meyer, Stephanie D. ;

Gore, Anu ;

Gu, Yan ;

Henkle, Brad ;

Hodous, Brian L. ;

Hsieh, Faye ;

Huang, Xin ;

Kim, Joseph L. ;

Lee, Josie H. ;

Martin, Matthew W. ;

Masse, Craig E. ;

McGowan, David C. ;

Metz, Daniela ;

Mohn, Deanna ;

Morgenstern, Kurt A. ;

Oliveira-dos-Santos, Antonio ;

Patel, Vinod F. ;

Powers, David ;

Rose, Paul E. ;

Schneider, Stephen ;

Tomlinson, Susan A. ;

Tudor, Yan-Yan ;

Turci, Susan M. ;

Welcher, Andrew A. ;

White, Ryan D. ;

Zhao, Huilin ;

Zhu, Li ;

Zhu, Xiaotian .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (19) :5671-5686

[8] ANGIOGENESIS IN CANCER, VASCULAR, RHEUMATOID AND OTHER DISEASE [J].

FOLKMAN, J .

NATURE MEDICINE, 1995, 1 (01) :27-31

[9]

Fong TAT, 1999, CANCER RES, V59, P99

[10]

Green L. S., 2011, ACS MED CHEM LETT, V2, P402

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