Functionalized analogues of 5,8,10-trideazafolate: development of an enzyme-assembled tight binding inhibitor of GAR Tfase and a potential irreversible inhibitor of AICAR Tfase.
A set of inhibitors 3 and 4 of GAR and AICAR Tfase based on the TDAF core which contain an sp2 C-10 carbon atom replacing N-10 of the natural cofactor are detailed. Both possess electrophilic olefins and the potential of trapping the reacting amine of the substrates GAR and AICAR by a Michael addition at the enzyme active site to provide an enzyme-assembled tight binding inhibitor. While these agents did not display such characteristics and served as simple competitive inhibitors of GAR Tfase and AICAR Tfase, inhibitor 15 prepared in the conversion of 3 to 4 may provide an enzyme-assembled tight binding inhibitor of GAR Tfase upon reaction with the substrate GAR and may inactivate AICAR Tfase by virtue of alkylation of an active site residue.
Boger
D L
DL
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Haynes
N E
NE
Warren
M S
MS
Ramcharan
J
J
Kitos
P A
PA
Benkovic
S J
SJ
D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D051026:Phosphoribosylglycinamide Formyltransferase; D011485:Protein Binding; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D004791:Enzyme Inhibitors; D005971:Glutamates; D011799:Quinazolines; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase