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Synthesis and biological evaluation of alpha- and gamma-carboxamide derivatives of 10-CF3CO-DDACTHF

Synthesis and biological evaluation of alpha- and gamma-carboxamide derivatives of 10-CF3CO-DDACTHF
Synthesis and biological evaluation of alpha- and gamma-carboxamide derivatives of 10-CF3CO-DDACTHF
Structurally-related, but non-polyglutamylatable, derivatives of 10-CF3CO-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 alpha-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (K(i) = 4.8 microM) and inactive in cellular functional assays, the gamma-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (K(i) = 0.056 microM) being only 4-fold less potent than 1 (K(i) = 0.015 microM). 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.
amides, chemistry *antineoplastic agents/chemical synthesis/pharmacology cell proliferation, drug effects drug screening assays, antitumor *enzyme inhibitors/chemical synthesis/pharmacology folic acid antagonists/chemical synthesis/pharmacology humans hydroxymethyl and formyl transferases/antagonists & inhibitors inhibitory concentration 50 molecular structure phosphoribosylaminoimidazolecarboxamide formyltransferase phosphoribosylglycinamide formyltransferase purines/antagonists & inhibitors, biosynthesis structure-activity relationship *tetrahydrofolates/chemical synthesis/chemistry/pharmacology tumor cells, cultured
0968-0896
3587-3592
Chong, Youhoon
e2730d88-537c-456c-ad50-38889c38cafc
Hwang, Inkyu
8ade2adf-15cf-4366-bac8-608048102ff0
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Zhang, Yan
8552a39d-0c4d-4712-8ad8-d0d5cc9d1779
Wilson, Ian A.
7865d500-d638-4a67-ad6d-fefad0ae83bb
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Boger, Dale L.
d81e0270-0561-47df-8904-85718bd462ff
Chong, Youhoon
e2730d88-537c-456c-ad50-38889c38cafc
Hwang, Inkyu
8ade2adf-15cf-4366-bac8-608048102ff0
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Zhang, Yan
8552a39d-0c4d-4712-8ad8-d0d5cc9d1779
Wilson, Ian A.
7865d500-d638-4a67-ad6d-fefad0ae83bb
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Boger, Dale L.
d81e0270-0561-47df-8904-85718bd462ff

Chong, Youhoon, Hwang, Inkyu, Tavassoli, Ali, Zhang, Yan, Wilson, Ian A., Benkovic, Stephen J. and Boger, Dale L. (2005) Synthesis and biological evaluation of alpha- and gamma-carboxamide derivatives of 10-CF3CO-DDACTHF. Bioorganic & Medicinal Chemistry, 13 (10), 3587-3592. (doi:10.1016/j.bmc.2004.11.050).

Record type: Article

Abstract

Structurally-related, but non-polyglutamylatable, derivatives of 10-CF3CO-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 alpha-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (K(i) = 4.8 microM) and inactive in cellular functional assays, the gamma-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (K(i) = 0.056 microM) being only 4-fold less potent than 1 (K(i) = 0.015 microM). 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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More information

Published date: 2005
Keywords: amides, chemistry *antineoplastic agents/chemical synthesis/pharmacology cell proliferation, drug effects drug screening assays, antitumor *enzyme inhibitors/chemical synthesis/pharmacology folic acid antagonists/chemical synthesis/pharmacology humans hydroxymethyl and formyl transferases/antagonists & inhibitors inhibitory concentration 50 molecular structure phosphoribosylaminoimidazolecarboxamide formyltransferase phosphoribosylglycinamide formyltransferase purines/antagonists & inhibitors, biosynthesis structure-activity relationship *tetrahydrofolates/chemical synthesis/chemistry/pharmacology tumor cells, cultured

Identifiers

Local EPrints ID: 45306
URI: https://eprints.soton.ac.uk/id/eprint/45306
ISSN: 0968-0896
PURE UUID: 67091416-65e0-43cf-86b7-c43220738b62
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 20 Mar 2007
Last modified: 14 Mar 2019 01:41

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