Discovery of platelet-type 12-human lipoxygenase selective inhibitors by high-throughput screening of structurally diverse libraries

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 22; pp. 6900 - 6908
• Main Authors: Deschamps, Joshua D., Gautschi, Jeffrey T., Whitman, Stephanie, Johnson, Tyler A., Gassner, Nadine C., Crews, Phillip, Holman, Theodore R.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.11.2007; Elsevier Science
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Blood Platelets - enzymology; Combinatorial Chemistry Techniques; Databases, Factual; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - statistics & numerical data; Dysidenin; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; High-throughput; Humans; IC 50; Isoenzymes - antagonists & inhibitors; Kinetics; Lipoxygenase; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Medical sciences; Michellamine B; Miscellaneous; Molecular Structure; NCI; Neodysidenin; Oxidoreductases; Pharmacology. Drug treatments; Reproducibility of Results; Structure-Activity Relationship; α-mangostin; High-throughput; Dysidenin; IC 50; α-mangostin; NCI; Neodysidenin; Kinetics; Lipoxygenase; Michellamine B; High throughput screening; Organic hydrazide; Halophenols; Nitrogen heterocycle; Thiazole derivatives; Selectivity; Diphenols; Pyridine derivatives; Structure activity relation; Chlorine Organic compounds; Chemical compound library; IC50; Bicyclic compound; Aromatic compound; Hydrazone; Human; Isoquinoline derivatives; Enzyme; Aminoamide; Organic ligand; Enzyme inhibitor; Natural compound; Naphthalene derivatives; α-Aminoacid; Platelet; Arachidonate 12-lipoxygenase; Phenols; Carboxamide; Benzenic compound; Oxidoreductases; Nickel II Complexes
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.08.015

15-hLO-1/12-hLO Inhibition ratios of selective inhibitors against platelet 12-hLO. Human lipoxygenases (hLO) have been implicated in a variety of diseases and cancers and each hLO isozyme appears to have distinct roles in cellular biology. This fact emphasizes the need for discovering selective hLO inhibitors for both understanding the role of specific lipoxygenases in the cell and developing pharmaceutical therapeutics. To this end, we have modified a known lipoxygenase assay for high-throughput (HTP) screening of both the National Cancer Institute (NCI) and the UC Santa Cruz marine extract library (UCSC-MEL) in search of platelet-type 12-hLO (12-hLO) selective inhibitors. The HTP screen led to the characterization of five novel 12-hLO inhibitors from the NCI repository. One is the potent but non-selective michellamine B, a natural product, anti-viral agent. The other four compounds were selective inhibitors against 12-hLO, with three being synthetic compounds and one being α-mangostin, a natural product, caspase-3 pathway inhibitor. In addition, a selective inhibitor was isolated from the UCSC-MEL (neodysidenin), which has a unique chemical scaffold for a hLO inhibitor. Due to the unique structure of neodysidenin, steady-state inhibition kinetics were performed and its mode of inhibition against 12-hLO was determined to be competitive ( K i = 17 μM) and selective over reticulocyte 15-hLO-1 ( K i 15-hLO-1/12-hLO > 30).