Proliferation inhibition of novel diphenylamine derivatives
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
PubMed
30453141
DOI
10.1016/j.bioorg.2018.10.063
PII: S0045-2068(18)30073-7
Knihovny.cz E-resources
- Keywords
- Antiproliferative, DNA binding study, DNA minor groove binder, Diphenylamine,
- MeSH
- Benzimidazoles chemistry MeSH
- NIH 3T3 Cells MeSH
- Diphenylamine analogs & derivatives chemical synthesis pharmacology MeSH
- DNA chemistry drug effects MeSH
- Fluorescent Dyes chemistry MeSH
- HEK293 Cells MeSH
- Intercalating Agents chemical synthesis chemistry pharmacology MeSH
- G1 Phase Cell Cycle Checkpoints drug effects MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Thermodynamics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Benzimidazoles MeSH
- bisbenzimide ethoxide trihydrochloride MeSH Browser
- Diphenylamine MeSH
- DNA MeSH
- Fluorescent Dyes MeSH
- Intercalating Agents MeSH
- Antineoplastic Agents MeSH
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs in the world but some NSAIDs such as diclofenac and tolfenamic acid display levels of cytotoxicity, an effect which has been attributed to the presence of diphenylamine contained in their structures. A novel series of diphenylamine derivatives were synthetised and evaluated for their cytotoxic activities and proliferation inhibition. The most active compounds in the cytotoxicity tests were derivative 6g with an IC50 value of 2.5 ± 1.1 × 10-6 M and derivative 6f with an IC50 value of 6.0 ± 3.0 × 10-6 M (L1210 cell line) after 48 h incubation. The results demonstrate that leukemic L1210 cells were much more sensitive to compounds 6f and 6g than the HEK293T cells (IC50 = 35 × 10-6 M for 6f and IC50 > 50 × 10-6 M for 6g) and NIH-3T3 (IC50 > 50 × 10-6 M for both derivatives). The IC50 values show that these substances may selectively kill leukemic cells over non-cancer cells. Cell cycle analysis revealed that a primary trend of the diphenylamine derivatives was to arrest the cells in the G1-phase of the cell cycle within the first 24 h. UV-visible, fluorescence spectroscopy and circular dichroism were used in order to study the binding mode of the novel compounds with DNA. The binding constants determined by UV-visible spectroscopy were found to be in the range of 2.1-8.7 × 104 M-1. We suggest that the observed trend for binding constant K is likely to be a result of different binding thermodynamics accompanying the formation of the complexes.
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