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 pyrroloiminoqui...

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Main Authors: Yo Kiichi, Koshiro Fukuoka, Anna Kitano, Koya Ishino, Naoyuki Kotoku
Format: Article
Language:English
Published: MDPI AG 2024-03-01
Series:Molecules
Subjects:
Online Access:https://www.mdpi.com/1420-3049/29/6/1389
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author Yo Kiichi
Koshiro Fukuoka
Anna Kitano
Koya Ishino
Naoyuki Kotoku
author_facet Yo Kiichi
Koshiro Fukuoka
Anna Kitano
Koya Ishino
Naoyuki Kotoku
author_sort Yo Kiichi
collection DOAJ
description 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 (IC<sub>50</sub> = 0.029 µM, selective index = 13.1), exceeding those of natural products.
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spelling doaj.art-d58e9ac208d54d97abc5b30539cc7b3b2024-03-27T13:57:15ZengMDPI AGMolecules1420-30492024-03-01296138910.3390/molecules29061389Unified Synthesis and Biological Evaluation of Makaluvamine J and Its AnalogsYo Kiichi0Koshiro Fukuoka1Anna Kitano2Koya Ishino3Naoyuki Kotoku4College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, JapanCollege of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, JapanCollege of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, JapanCollege of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, JapanCollege of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, JapanMakaluvamine 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 (IC<sub>50</sub> = 0.029 µM, selective index = 13.1), exceeding those of natural products.https://www.mdpi.com/1420-3049/29/6/1389Makaluvamine Jpancreatic canceranalog synthesisstructure-activity relationship
spellingShingle Yo Kiichi
Koshiro Fukuoka
Anna Kitano
Koya Ishino
Naoyuki Kotoku
Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs
Molecules
Makaluvamine J
pancreatic cancer
analog synthesis
structure-activity relationship
title Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs
title_full Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs
title_fullStr Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs
title_full_unstemmed Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs
title_short Unified Synthesis and Biological Evaluation of Makaluvamine J and Its Analogs
title_sort unified synthesis and biological evaluation of makaluvamine j and its analogs
topic Makaluvamine J
pancreatic cancer
analog synthesis
structure-activity relationship
url https://www.mdpi.com/1420-3049/29/6/1389
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