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Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway
Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway
The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, K(i) = 0.23 microM), 10-methanesulfonyl-5-DACTHF (2, K(i) = 0.58 microM), and 10-methylthio-DDACTHF (3, K(i) = 0.25 microM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC50 = 1.0 microM and 2, IC50 = 2.0 microM).
antineoplastic agents, chemical synthesis, pharmacology cell survival/drug effects *drug design enzyme inhibitors/chemical synthesis/chemistry/pharmacology evaluation studies humans hydroxymethyl and formyl transferases, antagonists & inhibitors inhibitory concentration 50 phosphoribosylaminoimidazolecarboxamide formyltransferase phosphoribosylglycinamide formyltransferase purines/antagonists & inhibitors/metabolism structure-activity relationship tetrahydrofolates, chemical synthesis/chemistry, pharmacology tumor cells, cultured
0968-0896
3577-3585
Cheng, Heng
d5528f70-6754-4bbd-a8fd-701c34350c33
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
Cheng, Heng
d5528f70-6754-4bbd-a8fd-701c34350c33
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

Cheng, Heng, Chong, Youhoon, Hwang, Inkyu, Tavassoli, Ali, Zhang, Yan, Wilson, Ian A., Benkovic, Stephen J. and Boger, Dale L. (2005) Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic & Medicinal Chemistry, 13 (10), 3577-3585. (doi:10.1016/j.bmc.2004.12.004).

Record type: Article

Abstract

The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, K(i) = 0.23 microM), 10-methanesulfonyl-5-DACTHF (2, K(i) = 0.58 microM), and 10-methylthio-DDACTHF (3, K(i) = 0.25 microM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC50 = 1.0 microM and 2, IC50 = 2.0 microM).

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More information

Published date: 2005
Keywords: antineoplastic agents, chemical synthesis, pharmacology cell survival/drug effects *drug design enzyme inhibitors/chemical synthesis/chemistry/pharmacology evaluation studies humans hydroxymethyl and formyl transferases, antagonists & inhibitors inhibitory concentration 50 phosphoribosylaminoimidazolecarboxamide formyltransferase phosphoribosylglycinamide formyltransferase purines/antagonists & inhibitors/metabolism structure-activity relationship tetrahydrofolates, chemical synthesis/chemistry, pharmacology tumor cells, cultured

Identifiers

Local EPrints ID: 45308
URI: https://eprints.soton.ac.uk/id/eprint/45308
ISSN: 0968-0896
PURE UUID: 551fb744-ecf6-45bd-a0be-68f1634fedca
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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