Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors

Guillermo A. Morales, Joseph R. Garlich, Jingdong Su, Xiaodong Peng, Jessica Newblom, Kevin Weber, Donald L. Durden

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway in a wide range of tumors has made PI3K a consensus target to inhibit as illustrated by more than 15 inhibitors now in clinical trials. Our previous work, built on the early pioneering multikinase inhibitor LY294002, resulted in the only PI3K vascular-targeted PI3K inhibitor prodrug, SF1126, which has now completed Phase I clinical trials. This inhibitor has properties that impart more in vivo activity than should be warranted by its enzymatic potency, which in general is much lower than other clinical stage PI3K inhibitors. We embarked on the exploration of scaffolds that retained such properties while simultaneously exhibiting an increased potency toward PI3K. This work resulted in the discovery of the 5-morpholino-7H-thieno[3,2-b]pyran-7-one system as the foundation of a new compound class of potential PI3K inhibitors having improved potency toward PI3K. The synthesis and cancer stem cell-based activity of these compounds are reported herein.

Original languageEnglish (US)
Pages (from-to)1922-1939
Number of pages18
JournalJournal of Medicinal Chemistry
Volume56
Issue number5
DOIs
StatePublished - Mar 14 2013

Fingerprint

Phosphatidylinositol 3-Kinase
Pyrans
Morpholinos
Neoplastic Stem Cells
Clinical Trials, Phase I
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Prodrugs
Blood Vessels
Clinical Trials

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors. / Morales, Guillermo A.; Garlich, Joseph R.; Su, Jingdong; Peng, Xiaodong; Newblom, Jessica; Weber, Kevin; Durden, Donald L.

In: Journal of Medicinal Chemistry, Vol. 56, No. 5, 14.03.2013, p. 1922-1939.

Research output: Contribution to journalArticle

Morales, Guillermo A. ; Garlich, Joseph R. ; Su, Jingdong ; Peng, Xiaodong ; Newblom, Jessica ; Weber, Kevin ; Durden, Donald L. / Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 5. pp. 1922-1939.
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