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
  • [41] Synthesis of Two New Heterocyclic Systems: Furo[3′,2′:5,6]pyrimido[2,1-c][1,2,4]triazines and Furo[3,2-e][1,2,3,4]tetrazolo[1,5-a]pyrimidine
    Rahimizadeh, M.
    Bakavoli, M.
    Gordi, Z.
    Seyedi, S. M.
    JOURNAL OF THE IRANIAN CHEMICAL SOCIETY, 2011, 8 (04) : 1135 - 1138
  • [42] Design, Synthesis, and Antitumor Activity of New N4-Alkyl-N2-Phenyl-Pyrrolo[3,2-d]Pyrimidine-2,4-Diamine Derivatives as CDK6 Inhibitors
    Huang, Chuanhui
    Wang, Shan
    Ma, Weifeng
    RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY, 2022, 48 (03) : 557 - 564
  • [43] Design, synthesis of new 3H-imidazo[4,5-b]pyridine derivatives and evaluation of their inhibitory properties as mixed lineage kinase 3 inhibitors
    Yoon, Hye Ree
    Balupuri, Anand
    Lee, Jinwoo
    Lee, Chaeeun
    Son, Dong-Hyun
    Jeoung, Re Gin
    Kim, Kyung ah
    Choi, Sungwook
    Kang, Nam Sook
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2024, 101
  • [44] Design and Synthesis of New [1,2,3]Triazolo[4,5-d]pyrimidine Derivatives as Potential Antiproliferative Agents
    Elkamhawy, Ahmed
    Al-Sanea, Mohammad M.
    Song, Chiman
    Sim, Taebo
    Roh, Eun Joo
    BULLETIN OF THE KOREAN CHEMICAL SOCIETY, 2015, 36 (07) : 1863 - 1873
  • [45] Synthesis and biological evaluation of 7H-pyrrolo [2,3-d] pyrimidine derivatives as potential p21-activated kinase 4 (PAK4) inhibitors
    Wang, Cong
    Xia, Jiawei
    Lei, Yan
    Lu, Rui
    Zhang, Mingliang
    Lv, He
    Hong, Qianqian
    Lu, Tao
    Chen, Yadong
    Li, Hongmei
    BIOORGANIC & MEDICINAL CHEMISTRY, 2022, 60
  • [46] Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors
    Li, Jieming
    Gu, Weijie
    Bi, Xinzhou
    Li, Huilan
    Liao, Chen
    Liu, Chunxia
    Huang, Wenlong
    Qian, Hai
    BIOORGANIC & MEDICINAL CHEMISTRY, 2017, 25 (24) : 6674 - 6679
  • [47] Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors
    Moradi, Mahfam
    Mousavi, Alireza
    Reznickova, Eva
    Peytam, Fariba
    Perina, Miroslav
    Vojackova, Veronika
    Firoozpour, Loghman
    Jorda, Radek
    Gruz, Jiri
    Emamgholipour, Zahra
    Sadat-Ebrahimi, Seyed Esmaeil
    Krystof, Vladimir
    Foroumadi, Alireza
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2024, 280
  • [48] Design, synthesis, and biological evaluation of novel pyrazolo [3,4-d] pyrimidine derivatives as potent PLK4 inhibitors for the treatment of TRIM37-amplified breast cancer
    Sun, Yin
    Sun, Yu
    Wang, Lin
    Wu, Tianxiao
    Yin, Wenbo
    Wang, Jingkai
    Xue, Yanli
    Qin, Qiaohua
    Sun, Yixiang
    Yang, Huali
    Zhao, Dongmei
    Cheng, Maosheng
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2022, 238
  • [49] Synthesis and Biological Evaluation of Novel 4-indolyl-5-phenyl(indolyl)-1,2-dihydropyrazol-3-ones as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors
    Yin, Hong
    Sui, Fengying
    Yang, Xinji
    Shangguan, Yingying
    Song, Guojie
    LETTERS IN DRUG DESIGN & DISCOVERY, 2012, 9 (08) : 780 - 788
  • [50] Novel 4-Acrylamido-Quinoline Derivatives as Potent PI3K/mTOR Dual Inhibitors: The Design, Synthesis, and in vitro and in vivo Biological Evaluation
    Ma, Xiaodong
    Shen, Li
    Zhang, Jiankang
    Liu, Guoqiang
    Zhan, Shuyu
    Ding, Baoyue
    Lv, Xiaoqing
    FRONTIERS IN CHEMISTRY, 2019, 7
12345