Toxicity and structure-activity relationship (SAR) of α,β-dehydroamino acids against human cancer cell lines.

Abstract

A library of N-protected dehydroamino acids, namely dehydroalanine, dehydroaminobutyric acid and dehydrophenylalanine derivatives, was screened in three human cancer cell lines [(lung (A549), gastric (AGS) and neuroblastoma (SH-SY5Y)] in order to characterize their toxicological profile and identify new molecules with potential anticancer activity. Results showed N-protected dehydrophenylalanine and dehydroaminobutyric acid derivatives have no or low toxicity for all tested cell lines. The N-protected dehydroalanines exhibit significant toxic effects and the AGS and SH-SY5Y cells were significantly more vulnerable than A549 cells. Four α,β-dehydroalanine derivatives, with IC50<62.5μM, were selected to investigate the pathways by which these compounds promote cell death. All compounds, at their IC50 concentrations, were able to induce apoptosis in both AGS and SH-SY5Y cell lines. In both cell lines, loss of mitochondrial membrane potential (ΔΨm) was found and caspase activity was increased, namely endoplasmic reticulum-resident caspase-4 in AGS cells and caspase-3/7 in SH-SY5Y cells. When evaluated in a non-cancer cell line, the molecules displayed no to low toxicity, thus suggesting some degree of selectivity for cancer cells. The results indicate that α,β-dehydroalanine derivatives can be considered a future resource of compounds able to work as anticancer drugs.

• Authors: Romeu A Videira, Paula B Andrade, Luís S Monteiro, Patrícia Valentão, Paula M T Ferreira, David M Pereira
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 47 Pg. 26-37 (Mar 2018) ISSN: 1879-3177 [Electronic] England
• PMID: 29107685 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Small Molecule Libraries
• Phenylalanine
• gamma-Aminobutyric Acid
• alpha, beta-dehydroaminobutyric acid
• Caspases
• Alanine

Topics

• Alanine (adverse effects, analogs & derivatives, chemistry, pharmacology)
• Antineoplastic Agents (adverse effects, chemistry, pharmacology)
• Apoptosis (drug effects)
• Caspases (chemistry, metabolism)
• Cell Line
• Cell Line, Tumor
• Cell Shape (drug effects)
• Drug Discovery
• Endoplasmic Reticulum (drug effects, enzymology)
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Molecular Structure
• Neuroblastoma (drug therapy, metabolism, pathology)
• Phenylalanine (adverse effects, analogs & derivatives, chemistry, pharmacology)
• Small Molecule Libraries
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Structure-Activity Relationship
• gamma-Aminobutyric Acid (adverse effects, analogs & derivatives, chemistry, pharmacology)