Asymmetric synthesis of inhibitors of glycinamide ribonucleotide transformylase.
Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors and has emerged as a productive target for antineoplastic therapeutic intervention. The asymmetric synthesis and evaluation of the two diastereomers of 10-methylthio-DDACTHF (10R-3 and 10S-3) and related analogues as potential inhibitors of GAR Tfase are reported. This work, which defines the importance of the C10 stereochemistry for this class of inhibitors of GAR Tfase, revealed that both diastereomers are potent inhibitors of rhGAR Tfase (10R-3 Ki = 210 nM, 10S-3 Ki = 180 nM) that exhibit effective cell growth inhibition (CCRF-CEM IC50 = 80 and 50 nM, respectively), which is dependent on intracellular polyglutamation by folylpolyglutamate synthetase (FPGS) but not intracellular transport by the reduced folate carrier.
DeMartino
Jessica K
JK
Department of Chemistry, The Scripps Research Institute,10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Hwang
Inkyu
I
Connelly
Stephen
S
Wilson
Ian A
IA
Boger
Dale L
DL
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D020128:Inhibitory Concentration 50; D010453:Peptide Synthases / Q000378:metabolism; D051026:Phosphoribosylglycinamide Formyltransferase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051026:Phosphoribosylglycinamide Formyltransferase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase