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

4-Morpholin-4-ylpyrido[3′,2′:4,5]thieno[3,2- d]pyrimidine 2a was discovered in our chemical library as a novel p110α inhibitor with an IC 50 of 1.4 μM. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3′,2′:4,5]furo[3,2- d]pyrimidine derivative 10e was discovered as a p110α inhibitor...

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Published in:Bioorganic & medicinal chemistry letters 2007-05, Vol.17 (9), p.2438-2442
Main Authors: 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
Format: Article
Language:English
Subjects:
Anti-cancer agent
Antineoplastic agents
Biological and medical sciences
General aspects
Inhibitor
Medical sciences
p110α
Pharmacology. Drug treatments
PI3 kinase
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Summary:4-Morpholin-4-ylpyrido[3′,2′:4,5]thieno[3,2- d]pyrimidine 2a was discovered in our chemical library as a novel p110α inhibitor with an IC 50 of 1.4 μM. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3′,2′:4,5]furo[3,2- d]pyrimidine derivative 10e was discovered as a p110α inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110β. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.02.032