Majusculamide D, isolated from the marine cyanobacterium Moorea producens, is an anticancer lipopentapeptide consisting of fatty acid, tripeptide, and pyrrolyl proline moieties. In this work, by utilizing a convergent synthetic approach, late-stage modification, and bioisostere strategy, 26 majusculamide D analogues were synthesized, and two (1i and 1j) demonstrated IC50 values < 1 nM against PANC-1 cancer cells. The results summarized a preliminary structure-activity relationship mainly at the C23, C4, C34, and C10 sites. A series of in vitro assays, including wound healing, transwell, clone formation, EdU, and western blot, confirmed that majusculamide D inhibited the migration, invasion, and proliferation of pancreatic cancer cells. The optimized fluorinated analogue 1n demonstrated a notable enhancement in stability during the mouse plasma assay (>50% left after 24 h), exhibited tumor-suppressive effects (51.5% at a dosage of 5 mg/kg), and successfully mitigated the severe toxicity (no mouse dead) observed in the group treated with majusculamide D (3 mice dead) in a xenografted mouse model.
Keywords: anticancer; metastasis; natural products; pancreatic cancer; structure-activity relationship.