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.
Highlights
The formation of only one diastereomer was observed by thin-layer chromatography (TLC) and proton nuclear magnetic resonance (1 H NMR)
A series of enantiopure tryptophanol-derived bicyclic lactams was prepared, and its antiproliferative activity was evaluated in AGS cells
From the first screening emerged compound 7c, a (R)-tryptophanol derivative with a para-chloro phenyl substituent, which was selected for further optimization
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cancer is considered a worldwide health problem, and its occurrence can be associated to a combination of environmental factors and genetic alterations [1]. According to the World Health Organization (WHO), it is estimated that in 2018, cancer contributed to. 9.5 million deaths worldwide [2]. Gastric cancer (GC) ranks third in the list of deadliest cancers [1], and its occurrence and mortality are highly influenced by region and culture [3]
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