title: A new acridine derivative induces cell cycle arrest and antiangiogenic effect on Ehrlich ascites carcinoma model.
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 LD50was 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.
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil. Electronic address: viviannemangueira@gmail.com.
authors.forename: Vivianne Mendes
authors.initials: VM
authors.lastname: Mangueira
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil. Electronic address: tatiannemota@gmail.com.
authors.forename: Tatianne Mota
authors.initials: TM
authors.lastname: Batista
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil. Electronic address: monalisa.brito@gmail.com.
authors.forename: Monalisa Taveira
authors.initials: MT
authors.lastname: Brito
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil. Electronic address: tatyannakelvia@hotmail.com.
authors.forename: Tatyanna Kelvia Gomes de
authors.initials: TKG
authors.lastname: Sousa
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil. Electronic address: ryldene@hotmail.com.
authors.forename: Ryldene Marques Duarte da
authors.initials: RMDD
authors.lastname: Cruz
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil. Electronic address: renataabrantes2@gmail.com.
authors.forename: Renata Albuquerque de
authors.initials: RA
authors.lastname: Abrantes
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil; Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil. Electronic address: robveras@msn.com.
authors.forename: Robson Cavalcanti
authors.initials: RC
authors.lastname: Veras
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil; Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil. Electronic address: isacmed@uol.com.br.
authors.forename: Isac Almeida de
authors.initials: IA
authors.lastname: Medeiros
authors.affiliation: Departamento de Morfologia, Universidade Federal do Rio Grande do Norte, 59078-970 Natal, RN, Brazil. Electronic address: karinapm@yahoo.com.
authors.forename: Karina Karla de Paula
authors.initials: KKP
authors.lastname: Medeiros
authors.affiliation: Laboratório de Sintese e Vetorização Molecular, Departamento de Farmácia, Universidade Estadual da Paraíba, 58429-500 Campina Grande, Paraíba, Brazil. Electronic address: analigia1_@hotmail.com.
authors.forename: Ana Ligia da Costa
authors.initials: ALDC
authors.lastname: Pereira
authors.affiliation: Laboratório de Sintese e Vetorização Molecular, Departamento de Farmácia, Universidade Estadual da Paraíba, 58429-500 Campina Grande, Paraíba, Brazil. Electronic address: vanessa.limaserafim@hotmail.com.
authors.forename: Vanessa de Lima
authors.initials: VL
authors.lastname: Serafim
authors.affiliation: Laboratório de Sintese e Vetorização Molecular, Departamento de Farmácia, Universidade Estadual da Paraíba, 58429-500 Campina Grande, Paraíba, Brazil. Electronic address: ricardo.olimpiodemoura@gmail.com.
authors.forename: Ricardo Olímpio de
authors.initials: RO
authors.lastname: Moura
authors.affiliation: Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil; Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil. Electronic address: mariannavbs@ltf.ufpb.br.
authors.forename: Marianna Vieira
authors.initials: MV
authors.lastname: Sobral
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001201:Ascites / Q000188:drug therapy* / Q000378:metabolism; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female
chemical_list: D000166:Acridines; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents
keywords: Acridine derivative; Angiogenesis; Antitumor activity; Cell cycle; Toxicity