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
  • [21] Design, Synthesis and Biological Evaluation of Novel Urea and Thiourea Bearing thieno[3,2-d]-pyrimidines as PI3 Kinase Inhibitors
    Bodige, Srinu
    Ravula, Parameshwar
    Gulipalli, Kali Charan
    Endoori, Srinivas
    Chandra, J. N. Narendra Sharath
    Cherukumalli, Purna Koteswara Rao
    Vanaja, G. R.
    Seelam, Nareshvarma
    ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, 2018, 18 (06) : 891 - 902
  • [22] A CONVENIENT SYNTHESIS FOR SOME NEW PYRIDO[3',2'/4,5]THIENO[3,2-D]PYRIMIDINE DERIVATIVES WITH POTENTIAL BIOLOGICAL-ACTIVITY
    PEINADOR, C
    OJEA, V
    QUINTELA, JM
    JOURNAL OF HETEROCYCLIC CHEMISTRY, 1992, 29 (07) : 1693 - 1702
  • [23] Synthesis of thiopyrano[4",3":4′,5′]pyrido[3′,2′:4, 5]furo[3,2-d]pyrimidines
    Ahmed, Essam Kh.
    Ameen, Mohamed A.
    CHINESE CHEMICAL LETTERS, 2010, 21 (06) : 669 - 673
  • [24] Discovery of novel pyrido[3,2-d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors
    Bai, Huanrong
    Sun, Jiajia
    Lei, Hao
    Zhang, San-Qi
    Yuan, Bo
    Ma, Mengyan
    Xin, Minhang
    DRUG DEVELOPMENT RESEARCH, 2023, 84 (08) : 1709 - 1723
  • [25] AN EFFICIENT IMINOPHOSPHORANE-MEDIATED SYNTHESIS FOR PYRIDO[3',2'4,5]THIENO[3,2-D] PYRIMIDINE-DERIVATIVES
    PEINADOR, C
    MOREIRA, MJ
    QUINTELA, JM
    TETRAHEDRON, 1994, 50 (22) : 6705 - 6714
  • [26] Synthesis and antimicrobial activity of new amino derivatives of pyrano[4", 3":4′, 5′]pyrido[3′, 2′: 4,5] thieno[3,2-d] pyrimidine
    Sirakanyan, Samvel N.
    Geronikaki, Athina
    Spinelli, Domenico
    Hakobyan, Elmira K.
    Kartsev, Viktor G.
    Petrou, Anthi
    Hovakimyan, Anush A.
    ANAIS DA ACADEMIA BRASILEIRA DE CIENCIAS, 2018, 90 : 1043 - 1057
  • [27] Synthesis of Cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine Derivatives. Dimroth Rearrangement of Triazolopyrimidines
    Paronikyan, E. G.
    Dashyan, Sh. Sh.
    RUSSIAN JOURNAL OF GENERAL CHEMISTRY, 2018, 88 (08) : 1623 - 1628
  • [28] Synthesis and Biological Activity of Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines as Phosphodiesterase Type 4 Inhibitors
    Taltavull, Joan
    Serrat, Jordi
    Gracia, Jordi
    Gavalda, Amadeu
    Andres, Miriam
    Cordoba, Monica
    Miralpeix, Montserrat
    Vilella, Dolors
    Beleta, Jorge
    Ryder, Hamish
    Pages, Lluis
    JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (19) : 6912 - 6922
  • [29] Synthesis of Cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine Derivatives. Dimroth Rearrangement of Triazolopyrimidines
    E. G. Paronikyan
    Sh. Sh. Dashyan
    Russian Journal of General Chemistry, 2018, 88 : 1623 - 1628
  • [30] Synthesis of pyrido[3′,2′ : 4,5]pyrrolo-and pyrido[3′,2′ : 4,5]thieno[3,2-d]pyrimidine derivatives using the Thorpe-Ziegler cyclization reaction
    Yakovlev M.Yu.
    Kadushkin A.V.
    Granik V.G.
    Pharmaceutical Chemistry Journal, 1997, 31 (7) : 350 - 353
12345