Probing Sponge-Derived Terpenoids for Human 15-Lipoxygenase Inhibitors

Abstract

A human 15-lipoxygenase (15-HLO) assay has been employed to discover new marine-sponge-derived bioactive compounds. Extracts from two different sponges, Jaspis splendens (order Choristida, family Jaspidae) and Suberea sp. (order Verongida, family Aplysinellidae), exhibited potent IC(50) values of 0.4 and 0.1 microg/mL, respectively. Both are sources of terpenoids, and the former is a known source of (+)-jasplakinolide (7), which is inactive as a 15-HLO inhibitor. The terpenoids included (+)-(5S,6S)-subersin (1, IC(50) > 100 microM), (-)-(5R,10R)-subersic acid (2, IC(50) = 15 microM), jaspaquinol (3, IC(50) = 0.3 microM), and (-)-jaspic acid (4, IC(50) = 1.4 microM). Structure elucidations and lipoxygenase activity studies of these compounds are reported.

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

“…The steady-state inhibitor kinetics were also performed in the 5 presence of 0.01% triton-X-100, which changed the inhibitor response of 15-hLO-1. In the presence of triton, baicalein showed linear mixed inhibition towards 15-hLO-1, similar to that with 12-hLO, with a 15 Without 0.01% triton-X-100 in the buffer, baicalein had an IC 50 of 0.64 ± 0.11µM against 12-hLO and 1.6 ± 0.24 µM against 15-hLO-1. Apigenin had an IC 50 of 81 ± 32 µM against 12-hLO and 3.4 ± 0.51µM against 15-hLO-1 ( Table 2).…”

“…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.…”

“…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 .…”

Short and efficient synthesis of (+)-subersic acids

“…by Crews and co-worker. 1 The natural product was an inhibitor of human 15-lipoxygenase, assay that has been employed to discover new marine-sponge derived bioactive compounds. The availability of inhibitors could provide biomolecules that are useful as pharmacological agents.…”

Development of a Fluorescent Intensity Assay Amenable for High-Throughput Screening for Determining 15-Lipoxygenase Activity

“…21 The importance of 15-LO-1 in several diseases has provoked numerous attempts to identify specific inhibitors, including screening of chemical compound libraries, virtual screening, and identification of natural products. [21][22][23][24][25][26][27][28][29][30][31][32] Especially interesting was the discovery of potent and cell-active 15-LO inhibitors that recently was described by Bristol-Myer-Squibb. 27 As part of our ongoing studies of the human 15-LO-1 enzyme, we have developed an enzyme-and a cell-based assay amenable for high-throughput screening (HTS).…”