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Eur J Med Chem. 2015 Oct 20;103:563-73. doi: 10.1016/j.ejmech.2015.09.012. Epub 2015 Sep 10.

Synthesis and biological evaluation of novel N-phenyl ureidobenzenesulfonate derivatives as potential anticancer agents. Part 2. Modulation of the ring B.

Author information

1
CHU de Québec Research Centre, Oncology Division, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Quebec City, QC, G1L 3L5, Canada; Faculty of Pharmacy, Laval University, Quebec City, QC, G1V 0A6, Canada.
2
CHU de Québec Research Centre, Oncology Division, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Quebec City, QC, G1L 3L5, Canada.
3
Genome Stability Laboratory, CHU de Québec Research Centre, Oncology Division, Hôtel-Dieu-de-Québec, 9 rue McMahon, Quebec City, QC, G1R 2J6, Canada; Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, G1V 0A6, Canada; FRQS Chercheur National Investigator, Canada.
4
CHU de Québec Research Centre, Oncology Division, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Quebec City, QC, G1L 3L5, Canada; Faculty of Pharmacy, Laval University, Quebec City, QC, G1V 0A6, Canada. Electronic address: sebastien.fortin@pha.ulaval.ca.

Abstract

DNA double strand-breaks (DSBs) are the most deleterious lesions that can affect the genome of living beings and are lethal if not quickly and properly repaired. Recently, we discovered a new family of anticancer agents designated as N-phenyl ureidobenzenesulfonates (PUB-SOs) that are blocking the cells cycle progression in S-phase and inducing DNA DSBs. Previously, we have studied the effect of several modifications on the molecular scaffold of PUB-SOs on their cytocidal properties. However, the effect of the nature and the position of substituents on the aromatic ring B is still poorly studied. In this study, we report the preparation and the biological evaluation of 45 new PUB-SO derivatives substituted by alkyl, alkoxy, halogen and nitro groups at different positions on the aromatic ring B. All PUB-SOs were active in the submicromolar to low micromolar range (0.24-20 μM). The cell cycle progression analysis showed that PUB-SOs substituted at position 2 by alkyl, halogen or nitro groups or substituted at position 4 by a hydroxyl group arrest the cell cycle progression in S-phase. Interestingly, all others PUB-SOs substituted at positions 3 and 4 arrested the cell cycle in G2/M-phase. PUB-SOs arresting the cell cycle progression in S-phase also induced the phosphorylation of H2AX (γH2AX) which is indicating the generation of DNA DSBs. We evidenced that few modifications on the ring B of PUB-SOs scaffold lead to cytocidal derivatives arresting the cell cycle in S-phase and inducing γH2AX and DSBs. In addition, this study shows that these new anticancer agents are promising and could be used as alternative to circumvent some of the biopharmaceutical complications that might be encountered during the development of PUB-SOs.

KEYWORDS:

Anticancer agents; DNA double strand-breaks; N-phenyl ureidobenzenesulfonates; PUB-SOs; S-phase arrest; γH2AX

PMID:
26408815
DOI:
10.1016/j.ejmech.2015.09.012
[Indexed for MEDLINE]

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