title: 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.
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).
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Cheng
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Ali
authors.initials: A
authors.lastname: Tavassoli
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Benkovic
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D051026:Phosphoribosylglycinamide Formyltransferase; D011687:Purines / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C503366:10-methanesulfonyl-5-DACTHF; C503368:10-methanesulfonyl-DDACTHF; C503367:10-methylthio-DDACTHF; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011687:Purines; D013763:Tetrahydrofolates; C045894:lometrexol; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase