Design and Synthesis of Marine-Inspired Itampolin A Derivatives to Overcome Chemoresistance in NSCLC via Cholesterol Homeostasis Modulation

Recent studies on brominated tyrosine-derived marine natural products have significantly expanded the library of known structures and revealed their potent and diverse antitumor mechanisms. Building upon our previous research on the natural product itampolin A isolated from marine sponges, we conducted structural optimizations and explored the structure--activity relationships (SARs) of novel scaffold derivatives concerning their inhibitory activities against lung cancer cells. In the present study, we further synthesized 15 novel derivatives, and compound <b>4l</b> demonstrated selective anti-proliferative activity against gefitinib-resistant PC9/GR cells, showing 4-fold greater potency compared to parental PC9 cells. Building on this finding, the present study aims to investigate the molecular mechanisms underlying the anti-proliferative effects of 4l in drug-resistant NSCLC models. Through cell cycle analysis, apoptosis assays, and signaling pathway evaluation, we seek to establish a theoretical foundation for developing novel therapeutic agents against chemotherapy-resistant lung cancer.