DOI: 10.3390/molecules29061389 ISSN: 1420-3049

Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs

Yo Kiichi, Koshiro Fukuoka, Anna Kitano, Koya Ishino, Naoyuki Kotoku
  • Chemistry (miscellaneous)
  • Analytical Chemistry
  • Organic Chemistry
  • Physical and Theoretical Chemistry
  • Molecular Medicine
  • Drug Discovery
  • Pharmaceutical Science

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 N-5 and N-9 yielded makaluvamine J and several analogs. A structure–activity relationship (SAR) analysis highlighted the significance of the lipophilic side chain at N-9 for the growth inhibitory activity of PANC-1 cells. The modest alkyl group at N-5 was found to improve selectivity against other cancer cells. Among the prepared analogs, the tryptamine analog 24 showed potent and selective cytotoxicity (IC50 = 0.029 µM, selective index = 13.1), exceeding those of natural products.

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