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

被引:3
作者
Espadinha, Margarida [1 ]
Barcherini, Valentina [1 ]
Goncalves, Lidia M. [1 ]
Molins, Elies [2 ]
Antunes, Alexandra M. M. [3 ]
Santos, Maria M. M. [1 ]
机构
[1] Univ Lisbon, Res Inst Med iMed ULisboa, Fac Pharm, Ave Prof Gama Pinto, P-1649003 Lisbon, Portugal
[2] Inst Ciencia Mat Barcelona ICMAB CSIC, Campus UAB, Bellaterra 08193, Spain
[3] ULisboa, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon, Portugal
关键词
anticancer agents; cytotoxicity; enantioselective synthesis; gastric adenocarcinoma; tryptophanol; METABOLIC STABILITY; EPIDEMIOLOGY; DISCOVERY; FUTURE; INDOLE;
D O I
10.3390/ph14030208
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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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页数:20
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