Macrocyclic lactones from seafood Amphioctopus neglectus: Newly described natural leads to attenuate angiotensin-II induced cardiac hypertrophy

Amphioctopus neglectus (Family: Octopodidae) is recognised as culinary delicacy in many cultures and a common sea food item on the Mediterranean and Asian coasts. Bioassay-directed fractionation of ethyl acetate/methanol extract of A. neglectus ensued in the characterisation of four previously undescribed macrocyclic lactones (1-4). These compounds exhibited potential radical-scavenging capacities (IC50 0.95-1.73 mM) along with anti-hypertensive activities (IC50 1.12-2.34 mM) against angiotensin converting enzyme (ACE). The optimum binding affinity of compound 2 (-9.84 kcal mol(-1)) bearing furo[1,4,8]trioxacyclohexadecine-12,19-dione moiety with ACE, along with its permissible hydrophobic-hydrophilic balance, manifested towards its greater anti-hypertensive activity compared to other analogues. The compound 2, with lesser values of the inhibitory constant (K-i = 1.0 mM) towards ACE, was found to bind more effectively to the enzyme in a non-competitive manner, and could describe the greater inhibitory ramifications than those displayed by other compounds (K-i > 1.1 mM). The ex-vivo studies revealed that compound 2 imparted protective effects against angiotensin-II induced cardiac hypertrophy at 25 mu g mL(-1) on H9C2 cell lines, wherein about 34 percent decrease in cell area with increase in viability could be attributed to anti-hypertrophic effects of the compound administrated. These results confirmed that the protective effect of the isolated macrocyclic lactones is mediated by enhancement of anti-oxidant defense systems, which subsequently attenuates the hypertensive related disorders.