Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

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...

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Published in:Bioorganic & medicinal chemistry 2003-10, Vol.11 (20), p.4511-4521
Main Authors: DESHARNAIS, Joel, INKYU HWANG, YAN ZHANG, TAVASSOLI, Ali, BABOVAL, Justin, BENKOVIC, Stephen J, WILSON, Ian A, BOGER, Dale L
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Folic Acid - analogs & derivatives
General aspects
Humans
Hydroxymethyl and Formyl Transferases - antagonists & inhibitors
Medical sciences
Pharmacology. Drug treatments
Phosphoribosylaminoimidazolecarboxamide Formyltransferase
Phosphoribosylglycinamide Formyltransferase
Purines - antagonists & inhibitors
Purines - biosynthesis
Structure-Activity Relationship
Tetrahydrofolates - chemistry
Tetrahydrofolates - pharmacology
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(03)00458-9