Design and synthesis of 4-methoxyphenylacetic acid esters as 15-lipoxygenase inhibitors and SAR comparative studies of them.
A group of 4-methoxyphenylacetic acid esters were designed, synthesized and evaluated as potential inhibitors of soybean 15-lipoxygenase (SLO) on the basis of eugenol and esteragol structures. Compounds 7d-e showed the best IC(50) in SLO inhibition (IC(50)=3.8 and 1.9 microM, respectively). All compounds were docked in SLO active site and showed that carbonyl group of compounds is oriented toward the Fe(III)-OH moiety in the active site of enzyme and fixed by hydrogen bonding with hydroxyl group. It is assumed that lipophilic interaction of ligand-enzyme would be in charge of inhibiting the enzyme activity. The selectivity of the synthetic esters in inhibiting of 15-HLOb was also compared with 15-HLOa by molecular modeling and multiple alignment techniques.
Sadeghian
Hamid
H
Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad 91389-13131, Iran. hd_sn@yahoo.com
Attaran
Neda
N
Jafari
Zeinab
Z
Saberi
Mohammad Reza
MR
Seyedi
Seyed Mohammad
SM
Eshghi
Hossein
H
Pordel
Mehdi
M
Riazi
Mohammad Mahdi
MM
D000595:Amino Acid Sequence; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004952:Esters; D016859:Lipoxygenase Inhibitors; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013025:Glycine max / Q000201:enzymology; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D004952:Esters; D016859:Lipoxygenase Inhibitors; D010648:Phenylacetates; D001093:Arachidonate 15-Lipoxygenase; C025136:phenylacetic acid