PMID- 13129587
OWN - NLM
STAT- MEDLINE
DCOM- 20040601
LR  - 20190901
IS  - 0968-0896 (Print)
IS  - 0968-0896 (Linking)
VI  - 11
IP  - 20
DP  - 2003 Oct 1
TI  - Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and 
      derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic 
      pathway.
PG  - 4511-21
AB  - The synthesis and evaluation of analogues and key derivatives of 10-CF3CO-DDACTHF 
      as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and 
      aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. 
      Polyglutamate analogues of 1 were evaluated as inhibitors of Escherichia coli and 
      recombinant human (rh) GAR Tfase, and AICAR Tfase. Although the pentaglutamate 6 
      was found to be the most active inhibitor of the series tested against rhGAR 
      Tfase (Ki=0.004 microM), little distinction between the mono-pentaglutamate 
      derivatives was observed (Ki=0.02-0.004 microM), suggesting that the principal 
      role of the required polyglutamation of 1 is intracellular retention. In 
      contrast, 1 and its defined polyglutamates 3-6 were much less inactive when 
      tested against rhAICAR Tfase (Ki=65-0.120 microM) and very selective (> or 
      =100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of 1 were 
      examined (7 and 8) and found to be much less active (1000-fold) highlighting the 
      exceptional characteristics of 1.
FAU - Desharnais, Joel
AU  - Desharnais J
AD  - Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines 
      Road, La Jolla, CA 92037, USA.
FAU - Hwang, Inkyu
AU  - Hwang I
FAU - Zhang, Yan
AU  - Zhang Y
FAU - Tavassoli, Ali
AU  - Tavassoli A
FAU - Baboval, Justin
AU  - Baboval J
FAU - Benkovic, Stephen J
AU  - Benkovic SJ
FAU - Wilson, Ian A
AU  - Wilson IA
FAU - Boger, Dale L
AU  - Boger DL
LA  - eng
GR  - CA 63536/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (10-(trifluoroacetyl)-5,10-dideazaacyclic-5,6,7,8-tetrahydrofolic acid)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Purines)
RN  - 0 (Tetrahydrofolates)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.1.2.- (Hydroxymethyl and Formyl Transferases)
RN  - EC 2.1.2.2 (Phosphoribosylglycinamide Formyltransferase)
RN  - EC 2.1.2.3 (Phosphoribosylaminoimidazolecarboxamide Formyltransferase)
SB  - IM
MH  - Drug Design
MH  - Enzyme Inhibitors/chemical synthesis/pharmacology
MH  - Folic Acid/*analogs & derivatives
MH  - Humans
MH  - Hydroxymethyl and Formyl Transferases/*antagonists & inhibitors
MH  - Phosphoribosylaminoimidazolecarboxamide Formyltransferase
MH  - Phosphoribosylglycinamide Formyltransferase
MH  - Purines/antagonists & inhibitors/*biosynthesis
MH  - Structure-Activity Relationship
MH  - Tetrahydrofolates/*chemistry/pharmacology
EDAT- 2003/09/18 05:00
MHDA- 2004/06/02 05:00
CRDT- 2003/09/18 05:00
PHST- 2003/09/18 05:00 [pubmed]
PHST- 2004/06/02 05:00 [medline]
PHST- 2003/09/18 05:00 [entrez]
AID - S0968089603004589 [pii]
AID - 10.1016/s0968-0896(03)00458-9 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2003 Oct 1;11(20):4511-21. doi: 10.1016/s0968-0896(03)00458-9.