Anti-hyperglycemic Δ5 steroids, marginoids A-C from marine veined octopus Amphioctopus marginatus (Octopodidae): Prospective natural leads inhibit serineexopeptidase dipeptidyl peptidase-4

Abstract

Three Δ⁵ steroid analogues, marginoids A-C were purified from the organic extract of marine veined octopus Amphioctopus marginatus (Taki, 1964) (family Octopodidae) distributed on the Asian and Mediterranean coasts. Their structures were elucidated as (5Z)-3β-acetoxy-cholesta-5-en-25-ethylene-22β-hydroxy-23,26-lactone (marginoid A), (5Z, 25Z)-3β-yl-(1'-(E)-3'-hydroxy-4'-methyl-hex-5'-enoate)-22-oxo-26-furanyl-cholesta-5,25-diene (marginoid B), and (5Z)-3β-yl-(7'-methoxypropan-8'-yl)-tetrahydro-2H-pyran-2-one-cholesta-5,24-dien (marginoid C) based on extensive spectroscopic experiments. Marginoid B with hydroxyl-methyl-hexanoate at the C-3 position in conjunction with the heterocyclic furanyl ring displayed superior anti-hyperglycemic properties as acknowledged by its promising serine protease dipeptidyl peptidase-4 attenuation potential (IC₅₀ 3.49 µM) displaying comparable activity with the standard DPP-4 inhibitor (DPP-4i) diprotin A (IC₅₀ 4.53 µM). The anti-hyperglycemic properties were corroborated by the promising antioxidant activities (IC₅₀ ∼ 0.8-1.0 mM) of these Δ⁵ steroids, marginoids A-C. Sizeably greater electronic properties, balanced hydrophobic-lipophilic properties (log P_OW 6.4-8.3), and comparatively lower steric factors were directly proportional to their bioactive properties. Molecular simulation studies in the binding sites of DPP-4 and lesser binding energy (-12.17 kcal/mol) and inhibition constant (Ki 1.20 nM) of marginoid B could be correlated with anti-hyperglycemic properties. Promising bioactivities of marginoid B isolated from A. marginatus are anticipated for nutraceutical applications against hyperglycemia.

Keywords: Anti-hyperglycemic; Dipeptidyl peptidase-4 inhibitor; Marginoids A-C; Marine veined octopus Amphioctopus marginatus (Taki, 1964); Octopodidae; Δ(5) steroid analogues.