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Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma

Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therape...

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Autores principales: Espadinha, Margarida, Barcherini, Valentina, Gonçalves, Lídia M., Molins, Elies, Antunes, Alexandra M. M., Santos, Maria M. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001353/
https://www.ncbi.nlm.nih.gov/pubmed/33801507
http://dx.doi.org/10.3390/ph14030208
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author Espadinha, Margarida
Barcherini, Valentina
Gonçalves, Lídia M.
Molins, Elies
Antunes, Alexandra M. M.
Santos, Maria M. M.
author_facet Espadinha, Margarida
Barcherini, Valentina
Gonçalves, Lídia M.
Molins, Elies
Antunes, Alexandra M. M.
Santos, Maria M. M.
author_sort Espadinha, Margarida
collection PubMed
description Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol-derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA-MB-231, A-549, DU-145, and MG-63). More importantly, the compounds were non-toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono- and di-hydroxylation of the indole ring.
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spelling pubmed-80013532021-03-28 Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma Espadinha, Margarida Barcherini, Valentina Gonçalves, Lídia M. Molins, Elies Antunes, Alexandra M. M. Santos, Maria M. M. Pharmaceuticals (Basel) Article Gastric cancer is one of the deadliest cancers in modern societies, so there is a high level of interest in discovering new drugs for this malignancy. Previously, we demonstrated the ability of tryptophanol-derived polycyclic compounds to activate the tumor suppressor protein p53, a relevant therapeutic target in cancer. In this work, we developed a novel series of enantiomerically pure tryptophanol-derived small molecules to target human gastric adenocarcinoma (AGS) cells. From an initial screening of fourteen compounds in AGS cell line, a hit compound was selected for optimization, leading to two derivatives selective for AGS gastric cells over other types of cancer cells (MDA-MB-231, A-549, DU-145, and MG-63). More importantly, the compounds were non-toxic in normal cells (HEK 293T). Additionally, we show that the growth inhibition of AGS cells induced by these compounds is mediated by apoptosis. Stability studies in human plasma and human liver microsomes indicate that the compounds are stable, and that the major metabolic transformations of these molecules are mono- and di-hydroxylation of the indole ring. MDPI 2021-03-02 /pmc/articles/PMC8001353/ /pubmed/33801507 http://dx.doi.org/10.3390/ph14030208 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Espadinha, Margarida
Barcherini, Valentina
Gonçalves, Lídia M.
Molins, Elies
Antunes, Alexandra M. M.
Santos, Maria M. M.
Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma
title Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma
title_full Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma
title_fullStr Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma
title_full_unstemmed Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma
title_short Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma
title_sort tryptophanol-derived oxazolopyrrolidone lactams as potential anticancer agents against gastric adenocarcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001353/
https://www.ncbi.nlm.nih.gov/pubmed/33801507
http://dx.doi.org/10.3390/ph14030208
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