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Tryptophanol-Derived Oxazolopyrrolidone Lactams as Potential Anticancer Agents against Gastric Adenocarcinoma
- Source :
- Digital.CSIC. Repositorio Institucional del CSIC, instname, Pharmaceuticals, Volume 14, Issue 3, Pharmaceuticals, Vol 14, Iss 208, p 208 (2021)
- Publication Year :
- 2021
- Publisher :
- Molecular Diversity Preservation International, 2021.
-
Abstract
- 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.<br />This research was funded by FCT (Fundação para a Ciência e a Tecnologia) through iMed.ULisboa (UIDB/04138/2020), CQE (UID/QUI/00100/2020), project PTDC/QUI-QOR/29664/ 2017, principal investigator grants CEECIND/02001/2017 (A. M. M. Antunes), and CEECIND/03143/ 2017 (L. M. Gonçalves), and PhD fellowships SFRH/BD/117931/2016 (M. Espadinha) and PD/BD/ 143126/2019 (V. Barcherini), and funded by Severo Ochoa FunFuture CEX2019-917-S.
- Subjects :
- 0301 basic medicine
Cytotoxicity
Tryptophanol
Pharmaceutical Science
lcsh:Medicine
lcsh:RS1-441
Article
lcsh:Pharmacy and materia medica
Enantioselective synthesis
03 medical and health sciences
chemistry.chemical_compound
anticancer agents
0302 clinical medicine
Drug Discovery
medicine
enantioselective synthesis
Gastric adenocarcinoma
lcsh:R
Cancer
tryptophanol
medicine.disease
Small molecule
030104 developmental biology
chemistry
Cell culture
Apoptosis
030220 oncology & carcinogenesis
Anticancer agents
Cancer cell
Cancer research
Microsome
Molecular Medicine
cytotoxicity
gastric adenocarcinoma
Growth inhibition
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Digital.CSIC. Repositorio Institucional del CSIC, instname, Pharmaceuticals, Volume 14, Issue 3, Pharmaceuticals, Vol 14, Iss 208, p 208 (2021)
- Accession number :
- edsair.doi.dedup.....2973922869b9565862e49adb31f07576