PMID- 12057663
OWN - NLM
STAT- MEDLINE
DCOM- 20030731
LR  - 20190901
IS  - 0968-0896 (Print)
IS  - 0968-0896 (Linking)
VI  - 10
IP  - 8
DP  - 2002 Aug
TI  - 10-Formyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid (10-formyl-DDACTHF): 
      a potent cytotoxic agent acting by selective inhibition of human GAR Tfase and 
      the de novo purine biosynthetic pathway.
PG  - 2739-49
AB  - The synthesis of 10-formyl-DDACTHF (3) as a potential inhibitor of glycinamide 
      ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide 
      ribonucleotide transformylase (AICAR Tfase) is reported. Aldehyde 3, the 
      corresponding gamma- and alpha-pentaglutamates 21 and 25 and related agents were 
      evaluated for inhibition of folate-dependent enzymes including GAR Tfase and 
      AICAR Tfase. The inhibitors were found to exhibit potent cytotoxic activity 
      (CCRF-CEM IC(50) for 3=60nM) that exceeded their enzyme inhibition potency [K(i) 
      (3)=6 and 1 microM for Escherichia coli GAR and human AICAR Tfase, respectively]. 
      Cytotoxicity rescue by medium purines, but not pyrimidines, indicated that the 
      potent cytotoxic activity is derived from selective purine biosynthesis 
      inhibition and rescue by AICAR monophosphate established that the activity is 
      derived preferentially from GAR versus AICAR Tfase inhibition. The potent 
      cytotoxic compounds including aldehyde 3 lost activity against CCRF-CEM cell 
      lines deficient in the reduced folate carrier (CCRF-CEM/MTX) or 
      folylpolyglutamate synthase (CCRF-CEM/FPGS(-)) establishing that their potent 
      activity requires both reduced folate carrier transport and polyglutamation. 
      Unexpectedly, the pentaglutamates displayed surprisingly similar K(i)'s versus E. 
      coli GAR Tfase and only modestly enhanced K(i)'s versus human AICAR Tfase. On the 
      surface this initially suggested that the potent cytotoxic activity of 3 and 
      related compounds might be due simply to preferential intracellular accumulation 
      of the inhibitors derived from effective transport and polyglutamation (i.e., ca. 
      100-fold higher intracellular concentrations). However, a subsequent examination 
      of the inhibitors against recombinant human GAR Tfase revealed they and the 
      corresponding gamma-pentaglutamates were unexpectedly much more potent against 
      the human versus E. coli enzyme (K(i) for 3, 14nM against rhGAR Tfase versus 6 
      microM against E. coli GAR Tfase) which also accounts for their exceptional 
      cytotoxic potency.
FAU - Marsilje, Thomas H
AU  - Marsilje TH
AD  - Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines 
      Road, La Jolla, CA 92037, USA.
FAU - Labroli, Marc A
AU  - Labroli MA
FAU - Hedrick, Michael P
AU  - Hedrick MP
FAU - Jin, Qing
AU  - Jin Q
FAU - Desharnais, Joel
AU  - Desharnais J
FAU - Baker, Stephen J
AU  - Baker SJ
FAU - Gooljarsingh, Lata T
AU  - Gooljarsingh LT
FAU - Ramcharan, Joseph
AU  - Ramcharan J
FAU - Tavassoli, Ali
AU  - Tavassoli A
FAU - Zhang, Yan
AU  - Zhang Y
FAU - Wilson, Ian A
AU  - Wilson IA
FAU - Beardsley, G Peter
AU  - Beardsley GP
FAU - Benkovic, Stephen J
AU  - Benkovic SJ
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-formyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Carrier Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Folate Receptors, GPI-Anchored)
RN  - 0 (Purines)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Tetrahydrofolates)
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)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.3.2.17 (folylpolyglutamate synthetase)
SB  - IM
MH  - Antineoplastic Agents/*chemical synthesis/pharmacology
MH  - Carrier Proteins/physiology
MH  - Cell Division/drug effects
MH  - Enzyme Inhibitors/chemical synthesis/pharmacology
MH  - Folate Receptors, GPI-Anchored
MH  - Humans
MH  - Hydroxymethyl and Formyl Transferases/*antagonists & inhibitors
MH  - Peptide Synthases/physiology
MH  - Phosphoribosylaminoimidazolecarboxamide Formyltransferase
MH  - Phosphoribosylglycinamide Formyltransferase
MH  - Purines/antagonists & inhibitors/*biosynthesis
MH  - *Receptors, Cell Surface
MH  - Structure-Activity Relationship
MH  - Tetrahydrofolates/*chemical synthesis
MH  - Tumor Cells, Cultured
EDAT- 2002/06/12 10:00
MHDA- 2003/08/02 05:00
CRDT- 2002/06/12 10:00
PHST- 2002/06/12 10:00 [pubmed]
PHST- 2003/08/02 05:00 [medline]
PHST- 2002/06/12 10:00 [entrez]
AID - S0968089602001025 [pii]
AID - 10.1016/s0968-0896(02)00102-5 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2002 Aug;10(8):2739-49. doi: 10.1016/s0968-0896(02)00102-5.