Xenicanes attenuate pro-inflammatory 5-lipoxygenase: Prospective natural anti-inflammatory leads from intertidal brown seaweed Padina tetrastromatica

Abstract

Two previously unreported xenicane class of novaxenicin-type xenicin diterpenoids (1–2) bearing cyclonona[d]furo [2,3-b]pyrandiol and three xeniolide-type diterpenoids with unprecedented octahydrocyclonona[c]pyran-3(1H)-one backbones (3–5) were separated from the organic extract of the intertidal seaweed Padina tetrastomatica (family Dictyotaceae), collected from southern India. The compounds were deduced to bear a xenicane moiety with a 2-oxabicyclo[7.4.0]tridecane cyclic system. The structures of these specialized metabolites were attributed based on the extensive nuclear magnetic resonance spectral analyses, and comparison of related compounds. Xeniolide-type diterpenes (3–5) registered significantly greater attenuation potential against pro-inflammatory 5-lipoxygenase (IC50 ~ 2.04 mM) than that exhibited by non-steroidal anti-inflammatory drug ibuprofen (IC50 4.50 mM, P< 0.05). The xeniolide derivative octahydro-1,7-dihydroxy-4-(41-hydroxy-42-methylpropyl)-6-(61-hydroxy-62-propenyl)-10-methyl-cyclonona[c]pyran-3(1H)-one (5) exhibited comparable antioxidant activity (DPPH IC50 1.73 mM) along with standard antioxidative agent α-tocopherol (IC50 < 2 mM). In silico molecular modelling studies were performed to designate the 5-lipoxygenase inhibitory mechanism of the xenicanes, and the comparison of docking parameters suggested that the xeniolide derivative 5 exhibited least binding energy of −11.56 kcal mol−1, and that was corroborated with its greater inhibition potential against the pro-inflammatory enzyme. These results demonstrated that the xeniolide-type diterpenoids with previously unreported δ-lactone cyclononane framework might constitute promising anti-inflammatory leads with pro-inflammatory 5-lipoxygenase enzyme inhibitory activities.