Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs.

Makaluvamine J, a pyrroloiminoquinone alkaloid of marine sponge origin, and its analogs were synthesized and assessed for their potential to develop as a novel and selective growth inhibitor targeting human pancreatic cancer PANC-1 cells. Ts-damirone B, a common precursor featuring a pyrroloiminoquinone core structure, was synthesized through Bartoli indole synthesis and IBX-mediated oxidation. Late-stage diversification at -5 and -9 yielded makaluvamine J and several analogs. A structure-activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at -9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at -5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog showed potent and selective cytotoxicity (IC = 0.029 µM, selective index = 13.1), exceeding those of natural products.