Biological Properties of New Chiral 2-Methyl-5,6,7,8-tetrahydroquinolin-8-amine-based Compounds

Our plain-English summary of Biological Properties of New Chiral 2-Methyl-5,6,7,8-tetrahydroquinolin-8-amine-based Compounds, by G. Facchetti, M.S. Christodoulou, L.B. Mendoza, et al (Molecules, 2020).

The study

• Authors: G. Facchetti, M.S. Christodoulou, L.B. Mendoza, F. Cusinato, L. Dalla Via, I. Rimoldi
• Journal: Molecules
• Published: 2020;25(23)
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The synthesis of a small library of 8-substituted 2-methyl-5,6,7,8-tetrahydroquinoline derivatives is presented. All the compounds were tested for their antiproliferative activity in non-cancer human dermal microvascular endothelial cells (HMEC-1) and cancer cells: human T-lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), human dermal microvascular endothelial cells (HMEC-1), colorectal adenocarcinoma (HT-29), ovarian carcinoma (A2780), and biphasic mesothelioma (MSTO-211H). Compounds 3a, 5a, and 2b, showing significant IC50 values against the whole panel of the selected cells, were further synthesized and tested as pure enantiomers in order to shed light on how their stereochemistry might impact on the related biological effect. The most active compound (R)-5a was able to affect cell cycle phases and to induce mitochondrial membrane depolarization and cellular ROS production in A2780 cells.

In plain English

This laboratory study involved neither asbestos nor people. The authors made twelve new tetrahydroquinoline-based compounds and tested in cell cultures how strongly each slowed cell growth. The cells were one non-cancer type and five cancer lines, including MSTO-211H, a biphasic mesothelioma line. Three compounds (3a, 5a and 2b) were then made as separate mirror-image forms (R and S). On ovarian cancer cells (A2780), concentrations halving cell numbers ranged from 5.4 µM for (R)-5a, the most effective, to 17.2 µM for (S)-5a. On the mesothelioma cells, (R)-5a gave 15.1 ± 1.5 µM, while (S)-5a and both forms of 2b exceeded 20 µM. HT-29 colorectal cancer cells appeared resistant to all six forms, with halving concentrations above 20 µM. In ovarian cancer cells, (R)-5a raised the share of cells in the G0/G1 cell-cycle phase. Separately, it depolarized mitochondria in about 20% of cells at 25 µM and about 30% at 50 µM. After 120 minutes at 50 µM, reactive oxygen species exceeded four times the level in untreated cells. The authors concluded that chirality matters in designing such drug candidates.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study: chemical synthesis of new compounds, cell-culture tests of their effect on cell growth, and mechanism experiments on the most active compound
• Who was studied: Human cell lines grown in the laboratory. The first screening used CEM (T-lymphocyte), HeLa (cervix carcinoma) and HMEC-1 (dermal microvascular endothelial cells). Further tests used HT-29 (colorectal adenocarcinoma), A2780 (ovarian carcinoma) and MSTO-211H (biphasic mesothelioma). Mechanism experiments used A2780 cells only. No human participants took part.
• Exposure: Cells were exposed to twelve newly synthesized compounds: six Schiff bases (1a–6a) and their six corresponding amines (1b–6b), first in racemic form. Compounds 3a, 5a and 2b were then tested as separate R and S enantiomers. No asbestos or fiber exposure was studied.
• Main results:
  • From the first screens, the authors selected compounds 3a, 5a and 2b for further study, stating that they exerted a significant cytotoxic effect against all the cancer cell lines. In racemic form, their IC50 values on MSTO-211H mesothelioma cells were 30 ± 8, 31 ± 7 and 35 ± 10 µM respectively (Table 2).
  • On A2780 ovarian carcinoma cells, all six enantiomers showed detectable growth inhibition, with IC50 values from 5.4 to 17.2 µM. (R)-5a was the most effective (5.4 ± 1.3 µM) and (S)-5a the least active (17.2 ± 3 µM).
  • On MSTO-211H biphasic mesothelioma cells, (R)-5a had an IC50 of 15.1 ± 1.5 µM, while (S)-5a was above 20 µM and appeared ineffective. (R)-3a and (S)-3a gave 14.9 ± 1.4 and 11.8 ± 2.3 µM. Both enantiomers of 2b were above 20 µM and were described as inactive.
  • HT-29 colorectal adenocarcinoma cells appeared resistant to all the enantiomers tested, with IC50 values above 20 µM. In the earlier racemic tests (Table 2), most compounds had measurable IC50 values on HT-29 cells, from 42 to 83 µM.
  • (R)-5a did not change the migration of supercoiled plasmid DNA and had no effect on topoisomerase I or II. The authors therefore excluded these molecules as targets for its growth-inhibiting effect.
  • In A2780 cells, (R)-5a produced a concentration-dependent increase in the G0/G1 cell cycle phase, from 57.3 ± 2.2% in untreated cells to 71.6 ± 0.7% at 20 µM. Over the same range, S phase fell from 27.5 ± 1.6% to 19.5 ± 0.4% and G2/M from 15.2 ± 1.8% to 9.0 ± 0.8%. These are mean values of four experiments.
  • In A2780 cells, (R)-5a caused mitochondrial depolarization in about 20% of cells at 25 µM and about 30% at 50 µM. The figure shows a representative experiment.
  • After 120 minutes, (R)-5a at 50 µM raised reactive oxygen species (ROS) in A2780 cells to more than 4-fold the level in untreated cells. The increase was concentration-dependent up to 25 µM and then appeared to plateau.
• The authors' conclusion: The authors concluded that the chiral center of compound 5a appeared significant for its activity. They wrote that the rise in ROS caused by (R)-5a suggests intracellular oxidative damage, likely mitochondria-mediated, that could contribute to its cytotoxic effect. They also concluded that (R)-5a, "even in an average level", highlights the importance of chirality in developing new drug candidates.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Colon cancer, Mesothelioma, Ovarian cancer.

Medical terms in this study, explained in our Lexicon: Carcinoma, Adenocarcinoma, Biphasic Mesothelioma.

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