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

doi:10.1016/j.bmcl.2007.02.032

Bioorganic & Medicinal Chemistry Letters

Volume 17, Issue 9, 1 May 2007, Pages 2438-2442

https://doi.org/10.1016/j.bmcl.2007.02.032 Get rights and content

Abstract

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 IC₅₀ 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.

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Acknowledgments

We thank Drs. K. Matsuda and N. Taniguchi for their advice and members of the Division of Analytical Research for performing instrumental analyses. We also thank Sonia Alex and Angela Hayes for help with the HPLC/MS/MS. This work was funded in part by Cancer Research UK [CUK] Programme Grant C308/A2187 and Paul Workman is a Cancer Research UK Life Fellow.

References and notes (31)

S.J. Leevers et al.
Curr. Opin. Cell Biol.
(1999)
T. Maehama et al.
Trends Cell Biol.
(1999)
L. Simpson et al.
Exp. Cell Res.
(2001)
J. Domin et al.
FEBS Lett.
(1997)
B. Vanhaesebroeck et al.
Exp. Cell Res.
(1999)
B. Vanhaesebroeck et al.
Trends Biochem. Sci.
(1997)
C.J. Vlahos et al.
J. Biol. Chem.
(1994)
S. Ward et al.
Chem. Biol.
(2003)
S.G. Ward et al.
Curr. Opin. Pharmacol.
(2003)
M. Hayakawa et al.
Bioorg. Med. Chem.
(2006)

M. Hayakawa et al.

Bioorg. Med. Chem.

(2007)

Z.A. Knight et al.

Cell

(2006)

Q.-W. Fan et al.

Cancer Cell

(2006)

M.A. Lawlor et al.

J. Cell Sci.

(2001)

B. Vanhaesebroeck et al.

Annu. Rev. Biochem.

(2001)

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

Abstract

Graphical abstract

Section snippets

Acknowledgments

Curr. Opin. Cell Biol.

Trends Cell Biol.

Exp. Cell Res.

FEBS Lett.

Exp. Cell Res.

Trends Biochem. Sci.

J. Biol. Chem.

Chem. Biol.

Curr. Opin. Pharmacol.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Cell

Cancer Cell

J. Cell Sci.

Annu. Rev. Biochem.