Synthesis and biological evaluation of pyrido[3′,2':4,5]furo [3,2-d]pyrimidine derivatives as novel PI3 kinase p110α inhibitors

被引：131
作者：
Hayakawa, Masahiko
Kaizawa, Hiroyuki
Moritomo, Hiroyuki
Koizumi, Tomonobu
Ohishi, Takahide
Yamano, Mayumi
Okada, Minoru
Ohta, Mitsuaki
Tsukamoto, Shin-ichi
Raynaud, Florence I.
Workman, Paul
Waterfield, Michael D.
Parker, Peter
机构：
[1] Astellas Pharma Inc, Drug Discovery Res, Tsukuba, Ibaraki 3002698, Japan
[2] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Sutton SN2 5NG, Surrey, England
[3] Ludwig Inst Canc Res, London W1W 7BS, England
[4] Canc Res UK London Res Inst, London WC2A 3PX, England
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 09期
关键词：
PI3; kinase; p110; alpha; inhibitor; anti-cancer agent;
D O I：
10.1016/j.bmcl.2007.02.032
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
4-Morpholin-4-ylpyrido[3 ',2 ':4,5]thieno[3,2-dlpyrimidine 2a was discovered in our chemical library as a novel pl Wa inhibitor with an IC50 of 1.4 mu M. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3 ',2 ':4,5]furo[3,2-dlpyrimidine derivative 10e was discovered as a p110 alpha inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110 beta. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice. (C) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2438 / 2442
页数：5
相关论文
共 50 条
  • [31] Design, Synthesis and Anticancer Activity of 4-Morpholinothieno[3,2-d]pyrimidine Derivatives Bearing Arylmethylene Hydrazine Moiety
    Zhu, Wufu
    Zhai, Xin
    Fu, Qiangqiang
    Guo, Fei
    Bai, Mei
    Wang, Jianqiang
    Wang, Haiyan
    Gong, Ping
    CHEMICAL & PHARMACEUTICAL BULLETIN, 2012, 60 (08) : 1037 - 1045
  • [32] One-pot synthesis of 4,6-diaryl-3-cyanopyridine-2(1H)-thiones and their transformation to substituted thieno[2,3-b;4,5-b]dipyridines and pyrido[3',2':4,5]thieno[3,2-d]pyrimidines
    Shestopalov, AM
    Nikishin, KG
    Gromova, AV
    Rodinovskaya, LA
    RUSSIAN CHEMICAL BULLETIN, 2003, 52 (10) : 2203 - 2206
  • [33] JAK3 inhibitors based on thieno[3,2-d]pyrimidine scaffold: design, synthesis and bioactivity evaluation for the treatment of B-cell lymphoma
    Chi, Fuyun
    Chen, Lixue
    Wang, Changyuan
    Li, Lei
    Sun, Xiuli
    Xu, Youjun
    Ma, Tengyue
    Liu, Kexin
    Ma, Xiaodong
    Shu, Xiaohong
    BIOORGANIC CHEMISTRY, 2020, 95
  • [34] Design and Synthesis of Novel 2,4-Diamino-5-pyrazol-4-yl Pyrimidine Derivatives as Selective Tyro3 Kinase Inhibitors
    Kim, Dukwoon
    Lee, Kyung Won
    Jung, Hyunseok
    Kim, Miok
    Lee, Joo-Youn
    Lee, Yeonkyung
    Hwang, Jong Yeon
    Min, Youngki
    Lee, Chang Hoon
    Cho, Sung Yun
    BULLETIN OF THE KOREAN CHEMICAL SOCIETY, 2018, 39 (09): : 1101 - 1104
  • [35] Design, Synthesis and Biological Evaluation of Novel Phenylsulfonylurea Derivatives as PI3K/mTOR Dual Inhibitors
    Zhao, Bingbing
    Lei, Fei
    Wang, Caolin
    Zhang, Binliang
    Yang, Zunhua
    Li, Wei
    Zhu, Wufu
    Xu, Shan
    MOLECULES, 2018, 23 (07):
  • [36] Synthesis and Anti-tumor Activity Evaluation of a Series of 2-or 4-Substituted Pyrido [3,2-d] pyrimidines as Nonclassical Antifolates
    Fang Fang
    Xue Liangmin
    Cong Jing
    Tian Chao
    Wang Xiaowei
    Liu Junyi
    Zhang Zhili
    CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE, 2019, 40 (10): : 2111 - 2120
  • [37] Design, synthesis, biological evaluation and docking studies of novel 2-substituted-4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d] pyrimidine derivatives as dual PI3Kα/mTOR inhibitors
    Lei, Fei
    Sun, Chengyu
    Xu, Shan
    Wang, Qinqin
    OuYang, Yiqiang
    Chen, Chen
    Xia, Hui
    Wang, Linxiao
    Zheng, Pengwu
    Zhu, Wufu
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2016, 116 : 27 - 35
  • [38] Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors
    Lv, Xiaoqing
    Ying, Huazhou
    Ma, Xiaodong
    Qiu, Ni
    Wu, Peng
    Yang, Bo
    Hu, Yongzhou
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2015, 99 : 36 - 50
  • [39] Synthesis and biological evaluation of substituted 1,2,3-benzotriazines and pyrido[3,2-d]-1,2,3-triazines as inhibitors of vascular endothelial growth factor receptor-2
    Zhao, Xing-Wang
    Liu, Dan
    Luan, Sheng-Lin
    Hu, Guo-Dong
    Lv, Jin-Ling
    Jing, Yong-Kui
    Zhao, Lin-Xiang
    BIOORGANIC & MEDICINAL CHEMISTRY, 2013, 21 (24) : 7807 - 7815
  • [40] Design, synthesis and biological evaluation of novel N-(methyl-d3) pyridazine-3-carboxamide derivatives as TYK2 inhibitors
    Liu, Fei
    Wang, Bin
    Liu, Yanlong
    Shi, Wei
    Hu, Zhongyuan
    Chang, Xiayun
    Tang, Xujing
    Zhang, Ying
    Xu, Hongjiang
    He, Ying
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2023, 86
12345