1. A new acridine derivative induces cell cycle arrest and antiangiogenic effect on Ehrlich ascites carcinoma model.
- Author
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Mangueira VM, Batista TM, Brito MT, Sousa TKG, Cruz RMDD, Abrantes RA, Veras RC, Medeiros IA, Medeiros KKP, Pereira ALDC, Serafim VL, Moura RO, and Sobral MV
- Subjects
- Animals, Apoptosis drug effects, Ascites metabolism, Carcinoma, Ehrlich Tumor metabolism, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Female, Acridines pharmacology, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents pharmacology, Ascites drug therapy, Carcinoma, Ehrlich Tumor drug therapy, Cell Cycle Checkpoints drug effects
- Abstract
Background: Acridine derivatives, including amsacrine, have antitumor activity. However, side effects, development of resistance and their low bioavailability, have limited their use. Herein, we described the synthesis, and evaluated the toxicity and antitumor activity of a new amsacrine analogous, the N'-(2-chloro-6-methoxy-acridin-9-yl)-2-cyano-3-(4-dimethylaminophenyl)-acrilohidrazida (ACS-AZ10)., Methods: The compound was obtained in a linear pathway where the ASC-Az intermediate was obtained by coupling of 6,9-dichloro-3-methoxy-acridine and 2-ciany-acethohidrazide followed by condensation with the corresponding aldehyde. The toxicity of ACS-AZ10 was evaluated in mice using acute toxicity and micronucleus assays. Ehrlich ascites carcinoma model was used to investigate the antitumor activity and toxicity of ACS-AZ10 (7.5, 15 or 30mg/kg, i.p.), after nine days of treatment. Cell cycle and angiogenesis were also evaluated., Results: The ASC-AZ10 was obtained with satisfactory yields and its structure was confirmed by spectroscopic and spectrometric techniques. On acute toxicity study, ACS-AZ10 (2000mg/kg, i.p.) induced transient depressant effects on central nervous system. The LD
50 was approximately 2500mg/kg. ACS-AZ10 (15 or 30mg/kg) displayed significant antitumor activity considering the tumor weight and volume, cell viability, and total Ehrlich cell count. ACS-AZ10 (7.5mg/kg) induced an increase in sub-G1 peak, suggesting apoptosis. At 15mg/kg ACS-AZ10 induced cell cycle arrest in G2/M phase and a reduction in the percentage of cells in G0/G1 and S phases, suggesting a pre-mitotic blockade. ACS-AZ10 reduced the microvessel density, indicating an antiangiogenic effect. Weak hematological, biochemical and histopathological toxicity were observed. The compound doesn't show genotoxicity in micronucleus assay., Conclusions: ACS-AZ10 has potent antitumor activity in vivo along with low toxicity., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)- Published
- 2017
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