PMID- 2299624
OWN - NLM
STAT- MEDLINE
DCOM- 19900309
LR  - 20190709
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 33
IP  - 2
DP  - 1990 Feb
TI  - Synthesis and biological activity of an acyclic analogue of 
      5,6,7,8-tetrahydrofolic acid, N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5- 
      pyrimidinyl)propyl]amino]-benzoyl]-L-glutamic acid.
PG  - 561-7
AB  - The synthesis and biological evaluation of 
      N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]- 
      benzoyl]-L-glutamic acid (1) (5-DACTHF, 543U76), an acyclic analogue of 
      5,6,7,8-tetrahydrofolic acid (THFA), are described. The key intermediate, 
      hemiaminal 8, was prepared in four stages from 3-chloropropionaldehyde diethyl 
      acetal. Reaction of 8 with dimethyl N-(4-aminobenzoyl)-L-glutamate gave the 
      2,4-bis(acetylamino) derivative 11, which was hydrolyzed with 1 N sodium 
      hydroxide to give 1; the glycine analogue 16 was prepared in a similar manner. 
      The N-methyl analogue 2 and N-formyl analogue 3 were prepared from 11 and 1, 
      respectively. Compounds 1-3 inhibited growth of Detroit 98 and L cells in cell 
      culture, with IC50s ranging from 2 to 0.018 microM. Cell culture toxicity 
      reversal studies and enzyme inhibition tests showed that 1 was cytotoxic but not 
      by the mechanism of the dihydrofolate reductase inhibitor aminopterin. Compound 1 
      and its polyglutamylated homologues inhibited glycinamide ribonucleotide 
      transformylase (GAR-TFase) and aminoimidazole ribonucleotide transformylase 
      (AICAR-TFase), the folate-dependent enzymes in de novo purine biosynthesis; and 1 
      was an effective substrate for mammalian folyl-polyglutamate synthetase. The 
      compound inhibited (IC50 = 20 nM) the conversion of [14C]formate to 
      [14C]-formylglycinamide ribonucleotide by MOLT-4 cells in culture. These data 
      suggest that the site of action of 1 is inhibition of purine de novo 
      biosynthesis. Moderate activity was observed against P388 leukemia in vivo.
FAU - Kelley, J L
AU  - Kelley JL
AD  - Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
FAU - McLean, E W
AU  - McLean EW
FAU - Cohn, N K
AU  - Cohn NK
FAU - Edelstein, M P
AU  - Edelstein MP
FAU - Duch, D S
AU  - Duch DS
FAU - Smith, G K
AU  - Smith GK
FAU - Hanlon, M H
AU  - Hanlon MH
FAU - Ferone, R
AU  - Ferone R
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Folic Acid Antagonists)
RN  - 0 (Purines)
RN  - 0 (Tetrahydrofolates)
RN  - 118252-44-1 
      (N-(4-((3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl)amino)benzoyl)glutamic 
      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)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.3.2.17 (folylpolyglutamate synthetase)
SB  - IM
EIN - J Med Chem 1990 Nov;33(11):3116
MH  - Acyltransferases/antagonists & inhibitors
MH  - Animals
MH  - Antimetabolites, Antineoplastic/*chemical synthesis/pharmacology
MH  - Cell Line
MH  - Chemical Phenomena
MH  - Chemistry
MH  - Folic Acid Antagonists/*chemical synthesis/pharmacology
MH  - *Hydroxymethyl and Formyl Transferases
MH  - Leukemia, Experimental/drug therapy
MH  - Mice
MH  - Peptide Synthases/metabolism
MH  - Phosphoribosylaminoimidazolecarboxamide Formyltransferase
MH  - Phosphoribosylglycinamide Formyltransferase
MH  - Purines/metabolism
MH  - Structure-Activity Relationship
MH  - Tetrahydrofolates/*chemical synthesis/pharmacology
EDAT- 1990/02/01 00:00
MHDA- 1990/02/01 00:01
CRDT- 1990/02/01 00:00
PHST- 1990/02/01 00:00 [pubmed]
PHST- 1990/02/01 00:01 [medline]
PHST- 1990/02/01 00:00 [entrez]
AID - 10.1021/jm00164a014 [doi]
PST - ppublish
SO  - J Med Chem. 1990 Feb;33(2):561-7. doi: 10.1021/jm00164a014.