Enhancing Aromaticity\nof Alkenylbenzenes May Decrease\nTheir Metabolic Activation and Reduce Their Potential Cytotoxicity:\nLessons Learnt from the Investigation of Myristicin and Elemicin

Metabolic\nactivation studies of lead compounds are a crucial step\nin drug development and offer a key consideration during rational\ndrug design. Myristicin (MRS) and elemicin (ELM), natural products\nbelonging to alkenylbenzenes, share the backbone of 1-allyl-3-methoxybenzene.\nThe backbone fuses with a methylenedioxy five-membered ring in MRS,\nwhile ELM is connected with two adjacent methoxy groups. ELM displayed\npowerful ability to induce cytotoxicity in cultured primary hepatocytes\nrelative to MRS. Additionally, ELM exhibited superior efficiency in\nmetabolic activation by CYP3A4, resulting in the formation of reactive\nmetabolites carbonium ion, epoxides, and α,β-unsaturated\nketone. Quantum chemical calculation and molecular dynamic studies\nrevealed that the fused methylenedioxy 5-membered ring enhances the\naromaticity of MRS, which affects the interaction between the allyl\nside chain and the heme for metabolic activation by the π–π\nstacking interaction with the aromatic amino acid residues of the\nhost enzyme.