title: Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity.
abstract: There is an urgent need to design and develop new and more potent EGFR inhibitors with improved anti-tumor activity. Here we describe the design and synthesis of two series of 4-benzothienyl amino quinazolines as new analogues of the EGFR inhibitor Gefitinib. The anti-tumor activity of these novel Gefitinib analogues in 6 human cancer cell lines was examined. Compared with the parental Gefitinib, most of the new compounds show a markedly increased cytotoxicity to cancer cells. Furthermore, several of the series B compounds that side chains at position 7 contain either a methyl or ethyl group are potent pan-RTK inhibitors. Two representative compounds in this class, 15 and 17, have an enhanced capability to inhibit cancer cell growth and induce apoptosis in vitro and inhibit tumor formation in vivo in human cancer cells with high HER-2, as compared with the parental Gefitinib. Thus they may be promising lead compounds to be developed as an alternative for current Gefitinib therapy or for Gefitinb-resistant patients, potentially via simultaneously blocking multiple RTK signaling pathways.
authors.affiliation: School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210009, Jiangsu, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wu
authors.forename: Mingdong
authors.initials: M
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Qu
authors.forename: Wenhua
authors.initials: W
authors.lastname: Tang
authors.forename: Youguang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jiqin
authors.initials: J
authors.lastname: Lian
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D066246:ErbB Receptors; D000077156:Gefitinib; D006801:Humans; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases
references.citation: Oncologist. 2005 Aug;10(7):461-6
references.pmid: 16079312
references.citation: Cancer. 2006 Sep 15;107(6):1207-18
references.pmid: 16909423
references.citation: Bioorg Med Chem Lett. 2006 Sep 15;16(18):4908-12
references.pmid: 16806916
references.citation: J Comput Aided Mol Des. 2003 Aug;17(8):475-93
references.pmid: 14703120
references.citation: Cancer Res. 2008 Nov 15;68(22):9479-87
references.pmid: 19010923
references.citation: J Med Chem. 1996 Jan 5;39(1):267-76
references.pmid: 8568816
references.citation: Exp Mol Pathol. 2008 Apr;84(2):79-89
references.pmid: 18279851
references.citation: N Engl J Med. 2005 Jul 14;353(2):123-32
references.pmid: 16014882
references.citation: Nat Rev Cancer. 2005 May;5(5):341-54
references.pmid: 15864276
references.citation: JAMA. 2003 Oct 22;290(16):2149-58
references.pmid: 14570950
references.citation: Mol Cancer Ther. 2008 Jul;7(7):2192-202
references.pmid: 18645028
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: Bioorg Med Chem Lett. 2004 Jan 5;14(1):111-4
references.pmid: 14684309
references.citation: Lancet Oncol. 2009 Jul;10(7):709-17
references.pmid: 19573800
references.citation: Mol Cancer Ther. 2005 Feb;4(2):197-205
references.pmid: 15713891
references.citation: J Med Chem. 1995 Sep 1;38(18):3482-7
references.pmid: 7658435
references.citation: J Clin Oncol. 2003 Jun 15;21(12):2237-46
references.pmid: 12748244
references.citation: Clin Cancer Res. 2008 Dec 1;14(23):7701-10
references.pmid: 19047096
references.citation: Mol Cell Endocrinol. 1990 May 7;70(3):205-16
references.pmid: 2193842
references.citation: N Engl J Med. 2005 Feb 24;352(8):786-92
references.pmid: 15728811
references.citation: ChemMedChem. 2007 Mar;2(3):318-32
references.pmid: 17206733
references.citation: J Med Chem. 2000 Aug 10;43(16):3199
references.pmid: 10956451
references.citation: Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1217-25
references.pmid: 19545787
references.citation: J Med Chem. 1999 May 20;42(10):1803-15
references.pmid: 10346932
references.citation: J Med Chem. 2000 Aug 24;43(17):3244-56
references.pmid: 10966743
references.citation: Oncologist. 2003;8(4):303-6
references.pmid: 12897327
references.citation: Bioorg Med Chem Lett. 2006 Sep 1;16(17):4686-91
references.pmid: 16777410
references.citation: Clin Cancer Res. 2006 Sep 15;12(18):5268-72
references.pmid: 17000658
references.citation: PLoS One. 2009 Aug 28;4(8):e6816
references.pmid: 19714243