Design, synthesis, and evaluation of novel 2-substituted 3-hydroxypyridin-4-ones: structure-activity investigation of metalloenzyme inhibition by iron chelators.
A range of novel 3-hydroxypyridin-4-ones with different R(2) substitutents has been synthesized for the investigation of the structure-activity relationship between the chemical nature of the ligand and the inhibitory activity of the iron-containing metalloenzyme 5-lipoxygenase. Results indicate that the molecular dimensions, together with the lipophilicity, have a critical impact on the ability of this class of chelator to inhibit 5-lipoxygenase. Hydrophilic ligands with a bulky R(2) substitutent tend to be weak inhibitors; thus 1,6-dimethyl-2-(4'-N-n-propylsuccinamido)methyl-3-hydroxypyridin-4(1H)-one (22b) which has the largest R(2) substitutent only caused 2% inhibition of the enzyme activity after 30 min incubation at 110 microM IBE (iron-binding equivalents), as compared with deferiprone which caused 40% inhibition of the enzyme activity, under the same conditions.
Liu
Zu D
ZD
Department of Pharmacy, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NN, UK.
Kayyali
Reem
R
Hider
Robert C
RC
Porter
John B
JB
Theobald
Anthony E
AE
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
C446947:1,6-dimethyl-2-(4'-N-n-propylsuccinamido)methyl-3-hydroxypyridin-4(1H)-one; D004791:Enzyme Inhibitors; D007502:Iron Chelating Agents; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D011728:Pyridones; D007501:Iron; D001094:Arachidonate 5-Lipoxygenase