PMID- 18686942
OWN - NLM
STAT- MEDLINE
DCOM- 20081024
LR  - 20211020
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 51
IP  - 17
DP  - 2008 Sep 11
TI  - Asymmetric synthesis of inhibitors of glycinamide ribonucleotide transformylase.
PG  - 5441-8
LID - 10.1021/jm800555h [doi]
AB  - 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.
FAU - DeMartino, Jessica K
AU  - DeMartino JK
AD  - Department of Chemistry, The Scripps Research Institute,10550 North Torrey Pines 
      Road, La Jolla, California 92037, USA.
FAU - Hwang, Inkyu
AU  - Hwang I
FAU - Connelly, Stephen
AU  - Connelly S
FAU - Wilson, Ian A
AU  - Wilson IA
FAU - Boger, Dale L
AU  - Boger DL
LA  - eng
GR  - P01 CA063536/CA/NCI NIH HHS/United States
GR  - P01 CA063536-09/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080808
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 2.1.2.2 (Phosphoribosylglycinamide Formyltransferase)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.3.2.17 (folylpolyglutamate synthetase)
SB  - IM
MH  - Antineoplastic Agents/*chemical synthesis
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Enzyme Inhibitors/*chemical synthesis
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Peptide Synthases/metabolism
MH  - Phosphoribosylglycinamide Formyltransferase/*antagonists & inhibitors
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
PMC - PMC2559975
MID - NIHMS57807
EDAT- 2008/08/09 09:00
MHDA- 2008/10/25 09:00
PMCR- 2009/09/11
CRDT- 2008/08/09 09:00
PHST- 2008/08/09 09:00 [pubmed]
PHST- 2008/10/25 09:00 [medline]
PHST- 2008/08/09 09:00 [entrez]
PHST- 2009/09/11 00:00 [pmc-release]
AID - 10.1021/jm800555h [doi]
PST - ppublish
SO  - J Med Chem. 2008 Sep 11;51(17):5441-8. doi: 10.1021/jm800555h. Epub 2008 Aug 8.