Molecules (Mar 2024)

Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs

  • Yo Kiichi,
  • Koshiro Fukuoka,
  • Anna Kitano,
  • Koya Ishino,
  • Naoyuki Kotoku

DOI
https://doi.org/10.3390/molecules29061389
Journal volume & issue
Vol. 29, no. 6
p. 1389

Abstract

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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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