Exploring Sponge-Derived Terpenoids for Their Potency and Selectivity against 12-Human, 15-Human, and 15-Soybean Lipoxygenases

• Published in: Journal of natural products (Washington, D.C.) Vol. 66; no. 2; pp. 230 - 235
• Main Authors: Amagata, Taro, Whitman, Stephanie, Johnson, Tyler A, Stessman, Chad C, Loo, Christopher P, Lobkovsky, Emil, Clardy, Jon, Crews, Phillip, Holman, Theodore R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.02.2003; Amer Chemical Soc; American Society of Pharmacognosy
• Subjects: Animals; aquatic invertebrates; Biological and medical sciences; chemical composition; chemistry; Chemistry, Medicinal; enzyme inhibitors; enzymology; General pharmacology; Glycine max; Glycine max - enzymology; Humans; Inhibitory Concentration 50; isolation & purification; Life Sciences & Biomedicine; linoleate 13S-lipoxygenase; Lipoxygenase Inhibitors; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - isolation & purification; Lipoxygenase Inhibitors - pharmacology; Medical sciences; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Oxidation-Reduction; Papua New Guinea; Pharmacognosy. Homeopathy. Health food; pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plant Sciences; Porifera; Porifera - chemistry; Science & Technology; soybeans; spectral analysis; stereochemistry; Structure-Activity Relationship; Terpenes; Terpenes - chemistry; Terpenes - isolation & purification; Terpenes - pharmacology; terpenoids; Papua New Guinea; Melanesia; Oceania; RESVERATROL; ACID; MECHANISM; 12-LIPOXYGENASE; SOYBEAN LIPOXYGENASE-1; 15-LIPOXYGENASE; 5-LIPOXYGENASE; INHIBITOR; SESTERTERPENE; MARINE NATURAL-PRODUCTS; Pentacyclic compound; Human; Terpenoid; Enzyme; Pharmacognosy; Enzyme inhibitor; Animal origin; Selectivity; Soybean; Oxygen heterocycle; In vitro; Biological activity; Marine environment; Acetal; Arachidonate 12-lipoxygenase; Porifera; Isolation; Oxidoreductases; Invertebrata; Sesterterpenes; Structural analysis; Arachidonate 15-lipoxygenase
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np020462l

To sharpen the search for new lipoxygenase inhibitors, we designed a screen to probe for both potency and selectivity. The assay utilized 12-human (12-HLO), 15-human (15-HLO), and 15-soybean (15-SLO) lipoxygenases. The IC50 value data obtained provided new insights about structure−activity relationships (SAR) for redox and nonredox inhibitors. All of the compounds tested were isolated from sponges and consisted of a novel terpenoid, hyrtenone A (1), and 12 known terpenoids. Potent compounds were defined as those having IC50 values < 1 μM, and selectivity was assessed from the three possible IC50 value ratios. One of the four terpenoid redox inhibitors studied, puupehenone (2), was equivalent to or better in potency than the well-known redox inhibitor nordihydroguarierate acid (NDGA, 14). However, none of the terpene redox inhibitors exhibited a selectivity ratio on a par with that of 14. Several potent nonredox inhibitors were identified, and one, dimethoxypuupehenol (5), exhibited notable selectivity. The structural elucidation of 1 and the SAR results for 13 natural products are reported. This study suggests that sponge-derived terpenes are a promising source for new lipoxygenase inhibitors.