TY - JOUR
T1 - Synthesis and biological evaluation of α- and γ-carboxamide derivatives of 10-CF3CO-DDACTHF
AU - Chong, Youhoon
AU - Hwang, Inkyu
AU - Tavassoli, Ali
AU - Zhang, Yan
AU - Wilson, Ian A.
AU - Benkovic, Stephen J.
AU - Boger, Dale L.
N1 - Funding Information:
We gratefully acknowledge the financial support of the National Institutes of Health (CA 63536, to DLB, SJB and IAW), and the Skaggs Institute for Chemical Biology.
PY - 2005/5/15
Y1 - 2005/5/15
N2 - Structurally-related, but non-polyglutamylatable, derivatives of 10-CF 3CO-DDACTHF (1), which incorporate l-glutamine (2) and l-isoglutamine (3) in place of l-glutamate, were prepared and evaluated as inhibitors of recombinant human (rh) GAR Tfase. While the l-glutamate α-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (Ki = 4.8 μM) and inactive in cellular functional assays, the γ-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (Ki = 0.056 μM) being only 4-fold less potent than 1 (K i = 0.015 μM). Moreover, 2 was effective in cellular functional assays exhibiting purine sensitive cytotoxic activity (IC50 = 300 nM, CCRF-CEM) only 20-fold less potent than 1 (IC50 = 16 nM), consistent with inhibition of de novo purine biosynthesis via selective inhibition of GAR Tfase. Like 1, 2 is transported into the cell by the reduced folate carrier. Unlike 1, the functional activity of 2 is not dependent upon FPGS polyglutamylation.
AB - Structurally-related, but non-polyglutamylatable, derivatives of 10-CF 3CO-DDACTHF (1), which incorporate l-glutamine (2) and l-isoglutamine (3) in place of l-glutamate, were prepared and evaluated as inhibitors of recombinant human (rh) GAR Tfase. While the l-glutamate α-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (Ki = 4.8 μM) and inactive in cellular functional assays, the γ-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (Ki = 0.056 μM) being only 4-fold less potent than 1 (K i = 0.015 μM). Moreover, 2 was effective in cellular functional assays exhibiting purine sensitive cytotoxic activity (IC50 = 300 nM, CCRF-CEM) only 20-fold less potent than 1 (IC50 = 16 nM), consistent with inhibition of de novo purine biosynthesis via selective inhibition of GAR Tfase. Like 1, 2 is transported into the cell by the reduced folate carrier. Unlike 1, the functional activity of 2 is not dependent upon FPGS polyglutamylation.
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U2 - 10.1016/j.bmc.2004.11.050
DO - 10.1016/j.bmc.2004.11.050
M3 - Article
C2 - 15848771
AN - SCOPUS:17444383044
SN - 0968-0896
VL - 13
SP - 3587
EP - 3592
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 10
ER -