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Potent Inhibitors of Phosphatidylinositol 3 (PI3) Kinase that have Antiproliferative Activity Only When Delivered as Prodrug Forms
Author(s) -
O'Brien Nathan J.,
Amran Syazwani,
Medan Jelena,
Cleary Ben,
Deady Leslie W.,
Jennings Ian G.,
Thompson Philip E.,
Abbott Belinda M.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200583
Subject(s) - prodrug , phosphatidylinositol , pi3k/akt/mtor pathway , ly294002 , kinase , chemistry , pharmacology , cell growth , enzyme , biochemistry , signal transduction , biology
Prodrugs for PI3K: A series of substituted analogues of the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 were prepared and found to potently inhibit the isolated enzyme but not MCF7 cell proliferation. Two tetrazolyl‐substituted analogues were further derivatized as prodrugs resulting in restoration of cell‐based activity. These data provide a conceptual model for development of tumor‐targeting prodrug forms of cell‐impermeable PI3K inhibitors.