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

Abstract

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 IC(50) 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 IC(50) values < 1 microM, and selectivity was assessed from the three possible IC(50) 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.

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

“…To date, we have characterized a number of inhibitors from both marine sponges and plants, however their selectivity is predominantly against reticulocyte 15-hLO-1 and not platelet 12-hLO. [14][15][16][17][18] This fact has inspired us to search further for 12-hLO selective inhibitors due to its well documented role in various human diseases. 7,[9][10][11] In the current paper, we investigated the flavonoids, baicalein and apigenin, as possible 12-hLO selective inhibitors, because, baicalein has been used in numerous citations as a selective inhibitor against 12-hLO in mammalian cells.…”

“…Finally, and most importantly, baicalein is not selective against platelet 12-hLO in the absence of detergents (15/ expressed/purified as described previously. 18 Iron contents of both lipoxygenase enzymes were determined using a Finnegan inductively coupled plasma mass spectrometer (ICP-MS), using cobalt-EDTA as an internal standard. LO iron concentrations were compared to standardized iron solutions.…”

“…For this reason and its well documented role in cancer progression, our laboratory has become increasingly interested in discovering selective platelet 12-hLO inhibitors. [14][15][16][17][18][19][20] Plant extracts are a rich source of LO inhibitors 16,[21][22][23] and one particular class, the flavonoids, is relatively nontoxic, phenolic, and potent against LO. 16,[24][25][26][27] In addition, flavonoids have been shown to have antioxidant 24, 28 , anti-inflammatory 26,29 , antitumor 30 , antimicrobial 31 and antiviral properties 32 .…”

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

“…A similar effect was seen previously in our laboratories, where hyrtenone A, which is selective against 12-hLO, is over 10-fold less potent than its analogue, puupehenone, a selective 15-hLO-1 inhibitor. 29 The potency and selectivity of neodysidenin against 12-hLO versus 15-hLO-1 make it a novel class of LO inhibitor that could potentially be optimized by further structural modifications to increase its potency against 12-hLO, while maintaining its high selectivity. In addition, it will be important to determine whether neodysidenin is also selective against platelet-type 12-hLO versus leukocyte and epidermal 12-hLO.…”

Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida

“…Puupehenone (14) showed a better activity to 12-human, 15-human and 15-soybean lipoxygenases than the well known redox inhibitor nordihydroguaiaretic acid [111]. It behaves as a redox inhibitor, reducing the iron site.…”