biostudies-literatureKiichi Ythe Research Promotion Program for Acquiring KAKENHI, Ritsumeikan UniversityJapan Society for the Promotion of Science1389https://www.ebi.ac.uk/biostudies/studies/S-EPMC10976149biostudies-literatureUnknown29(6)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 <i>N</i>-5 and <i>N</i>-9 yielded makaluvamine J and several analogs. A structure-activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at <i>N</i>-9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at <i>N</i>-5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog <b>24</b> showed potent and selective cytotoxicity (IC₅₀ = 0.029 µM, selective index = 13.1), exceeding those of natural products.Molecules (Basel, Switzerland)Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs.PMC1097614922K05339B21-0051Ishino KKiichi YFukuoka KKotoku NKitano AfalseUnified 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 <i>N</i>-5 and <i>N</i>-9 yielded makaluvamine J and several analogs. A structure-activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at <i>N</i>-9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at <i>N</i>-5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog <b>24</b> showed potent and selective cytotoxicity (IC₅₀ = 0.029 µM, selective index = 13.1), exceeding those of natural products.2024-01-01T00:00:00Z2024 Mar2025-04-26T11:31:20.846Z2025-04-06T13:41:02.731ZS-EPMC109761493854302510.3390/molecules29061389