Inosine-5'-monophosphate analogues as inhibitors of human IMP cyclohydrolase and cellular growth.
The catalytic mechanism for the enzyme, IMP cyclohydrolase, may involve a reaction intermediate with negative charge in the 2-position of the purine ring (Szabados, E., Hindmarsh, E., Phillips, L., Duggleby, R.G. & Christopherson, R.I. (1994) Biochemistry 33, 14237-14245). Three analogues of IMP have been synthesised where fluorine, chlorine or bromine has been substituted in the 2-position on the purine ring. These analogues with an electronegative substituent may resemble a reaction intermediate for IMP cyclohydrolase; 2-fluoro IMP is a potent inhibitor of the enzyme with a Ki value of 0.19 microM, while 2-chloro IMP has a Ki of 1.9 microM and 2-bromo IMP is not inhibitory. However, IMP cyclohydrolase is not inhibited in human CCRF-CEM leukaemia cells exposed to 2-fluoro inosine although it is toxic to these cells with an IC50 value of 4.9 microM.
Szabados
E
E
Department of Biochemistry, University of Sydney, NSW, Australia.
Manthey
M K
MK
Wilson
P K
PK
Christopherson
R I
RI
D001966:Bromine; D002455:Cell Division / Q000187:drug effects; D002713:Chlorine; D003848:Deoxyguanine Nucleotides / Q000096:biosynthesis; D003853:Deoxyribonucleosides / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005461:Fluorine; D006801:Humans; D007291:Inosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology; D009705:Nucleosides / Q000096:biosynthesis; D009709:Nucleotide Deaminases / Q000037:antagonists & inhibitors*; D010710:Phosphates / Q000378:metabolism; D011687:Purines / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D003848:Deoxyguanine Nucleotides; D003853:Deoxyribonucleosides; D004791:Enzyme Inhibitors; D009705:Nucleosides; D010710:Phosphates; D011687:Purines; D007291:Inosine Monophosphate; D005461:Fluorine; D002713:Chlorine; C029603:deoxyguanosine triphosphate; D009709:Nucleotide Deaminases; C021436:IMP cyclohydrolase; D001966:Bromine