title: Protein structure-based design, synthesis, and biological evaluation of 5-thia-2,6-diamino-4(3H)-oxopyrimidines: potent inhibitors of glycinamide ribonucleotide transformylase with potent cell growth inhibition.
abstract: The design, synthesis, biochemical, and biological evaluation of a novel series of 5-thia-2,6-diamino-4(3H)-oxopyrimidine inhibitors of glycinamide ribonucleotide transformylase (GART) are described. The compounds were designed using the X-ray crystal structure of human GART. The monocyclic 5-thiapyrimidinones were synthesized by coupling an alkyl thiol with 5-bromo-2, 6-diamino-4(3H)-pyrimidinone, 20. The bicyclic compounds were prepared in both racemic and diastereomerically pure forms using two distinct synthetic routes. The compounds were found to have human GART KiS ranging from 30 microM to 2 nM. The compounds inhibited the growth of both L1210 and CCRF-CEM cells in culture with potencies down to the low nanomolar range and were found to be selective for the de novo purine biosynthesis pathway. The most potent inhibitors had 2,5-disubstituted thiophene rings attached to the glutamate moiety. Placement of a methyl substituent at the 4-position of the thiophene ring to give compounds 10, 18, and 19 resulted in inhibitors with significantly decreased mFBP affinity.
authors.affiliation: Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Varney
authors.forename: C L
authors.initials: CL
authors.lastname: Palmer
authors.forename: W H
authors.initials: WH
authors.lastname: Romines
authors.forename: T
authors.initials: T
authors.lastname: Boritzki
authors.forename: S A
authors.initials: SA
authors.lastname: Margosiak
authors.forename: R
authors.initials: R
authors.lastname: Almassy
authors.forename: C A
authors.initials: CA
authors.lastname: Janson
authors.forename: C
authors.initials: C
authors.lastname: Bartlett
authors.forename: E J
authors.initials: EJ
authors.lastname: Howland
authors.forename: R
authors.initials: R
authors.lastname: Ferre
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli; D005492:Folic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases; D051379:Mice; D008958:Models, Molecular; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D051026:Phosphoribosylglycinamide Formyltransferase; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011994:Recombinant Proteins; C092738:10-formyl-5,8-dideazafolate; D005492:Folic Acid; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D000217:Acyltransferases