Preparation, characterisation and biological evaluation of new N-phenyl amidobenzenesulfonates and N-phenyl ureidobenzenesulfonates inducing DNA double-strand breaks. Part 3. Modulation of ring A
| Autor: | Chahrazed Bouzriba, Marvin Godard, Sébastien Fortin, Mathieu Gagné-Boulet |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
DNA damage Stereochemistry Antineoplastic Agents Ring (chemistry) Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Tumor Cells Cultured medicine Humans Moiety DNA Breaks Double-Stranded Cell Proliferation Pharmacology Dose-Response Relationship Drug Molecular Structure Benzenesulfonates Organic Chemistry Biological activity General Medicine Cell cycle enzymes and coenzymes (carbohydrates) DNA Alkylation 030104 developmental biology chemistry Mechanism of action 030220 oncology & carcinogenesis bacteria Drug Screening Assays Antitumor medicine.symptom DNA |
| Zdroj: | European Journal of Medicinal Chemistry. 155:681-694 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.06.030 |
| Popis: | N-Phenyl ureidobenzenesulfonates (PUB-SOs) are a new class of anticancer agents blocking the cell cycle progression in S-phase, inducing replicative stress and DNA double-strand breaks (DSBs). In this study, we evaluate the effect of modifying the nature and the position of different substituents on ring A of PUB-SOs on the antiproliferative activity, pharmacological activity as well as on calculated physicochemical, pharmacokinetics and drug-likeness properties. Modification of the urea group by an amide group led to new PUB-SO analogs designated as N-phenyl amidobenzenesulfonates (PAB-SOs). The 2-chloroethyl moiety on ring A was also substituted by different alkyl, cycloalkyl and chloroalkyl groups. The new PAB-SOs and PUB-SOs blocking the cell cycle progression in S-phase exhibit antiproliferative activity in the submicromolar to low micromolar range (0.14–27 μM) on four human cancer cell lines, namely HT-1080, HT-29, M21 and MCF7. Moreover, selected PUB-SO and PAB-SO derivatives induced the phosphorylation of H2AX in M21 cells and do not exhibit or only slightly alkylating activity as confirmed by the 4-(4-nitrobenzyl)pyridine (NBP) assay. Finally, our results show that structure modifications weakly affect the calculated physicochemical, pharmacokinetics and drug-likeness properties of PAB-SOs and PUB-SOs. Therefore, PAB-SOs and PUB-SOs are promising anticancer agents inducing replicative stress and DNA damage via a mechanism of action unrelated to DNA alkylation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect