Monoaryl- and bisaryldihydroxytropolones as potent inhibitors of inositol monophosphatase.
The first successful preparation of mono- and disubstituted 3,7-dihydroxytropolone involves a four-step synthetic scheme. Thus, bromination of 3,7-dihydroxytropolone (8) followed by permethylation of the resultant products furnished gram quantities of intermediates 13-18. Single or double Suzuki coupling reactions between these permethylated monobromo- and dibromodihydroxytropolone derivatives and a variety of boronic acids delivered the expected products whose deprotection yielded the desired compounds 1a-u and 26a-n, usually in fair to good yields. Tropolones 1 and 26 were found to be potent inhibitors of inositol monophosphatase with IC50 values in the low-micromolar range. The results are discussed in the context of the recently described novel mode of inhibition of the enzyme by 3,7-dihydroxytropolones.
Piettre
S R
SR
Marion Merrell Research Institute, Strasbourg, France. Serge.Piettre@osiris.univ-rouen.fr
André
C
C
Chanal
M C
MC
Ducep
J B
JB
Lesur
B
B
Piriou
F
F
Raboisson
P
P
Rondeau
J M
JM
Schelcher
C
C
Zimmermann
P
P
Ganzhorn
A J
AJ
D001665:Binding Sites; D004164:Diphosphonates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014334:Tropolone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D011994:Recombinant Proteins; C079103:L 690330; C002647:inositol 1-phosphate; D014334:Tropolone; C057099:3,7-dihydroxytropolone; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase