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

Heng Cheng; Youhoon Chong; Inkyu Hwang; Ali Tavassoli; Yan Zhang; Ian A Wilson; Stephen J Benkovic; Dale L Boger

doi:10.1016/j.bmc.2004.12.004

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

Bioorg Med Chem. 2005 May 16;13(10):3577-85. doi: 10.1016/j.bmc.2004.12.004.

Authors

Heng Cheng¹, Youhoon Chong, Inkyu Hwang, Ali Tavassoli, Yan Zhang, Ian A Wilson, Stephen J Benkovic, Dale L Boger

Affiliation

¹ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

PMID: 15848770
DOI: 10.1016/j.bmc.2004.12.004

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).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Cell Survival / drug effects
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Evaluation Studies as Topic
Humans
Hydroxymethyl and Formyl Transferases / antagonists & inhibitors*
Inhibitory Concentration 50
Phosphoribosylaminoimidazolecarboxamide Formyltransferase
Phosphoribosylglycinamide Formyltransferase
Purines / antagonists & inhibitors
Purines / metabolism
Structure-Activity Relationship
Tetrahydrofolates / chemical synthesis*
Tetrahydrofolates / chemistry
Tetrahydrofolates / pharmacology*
Tumor Cells, Cultured

Substances

10-methanesulfonyl-5-DACTHF
10-methanesulfonyl-DDACTHF
10-methylthio-DDACTHF
Antineoplastic Agents
Enzyme Inhibitors
Purines
Tetrahydrofolates
lometrexol
Hydroxymethyl and Formyl Transferases
Phosphoribosylglycinamide Formyltransferase
Phosphoribosylaminoimidazolecarboxamide Formyltransferase

Grants and funding

CA 63536/CA/NCI NIH HHS/United States