Vivianne Mendes Mangueira1, Tatianne Mota Batista2, Monalisa Taveira Brito3, Tatyanna Kelvia Gomes de Sousa4, Ryldene Marques Duarte da Cruz5, Renata Albuquerque de Abrantes6, Robson Cavalcanti Veras7, Isac Almeida de Medeiros8, Karina Karla de Paula Medeiros9, Ana Ligia da Costa Pereira10, Vanessa de Lima Serafim11, Ricardo Olímpio de Moura12, Marianna Vieira Sobral13. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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. 7. 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. 8. 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. 9. Departamento de Morfologia, Universidade Federal do Rio Grande do Norte, 59078-970 Natal, RN, Brazil. Electronic address: karinapm@yahoo.com. 10. Laboratório de Sintese e Vetorização Molecular, Departamento de Farmácia, Universidade Estadual da Paraíba, 58429-500 Campina Grande, Paraíba, Brazil. Electronic address: analigia1_@hotmail.com. 11. 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. 12. 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. 13. 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.
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 LD50 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.
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 LD50 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.
Authors: Jelena Rupar; Vladimir Dobričić; Jelena Grahovac; Siniša Radulović; Žiga Skok; Janez Ilaš; Mara Aleksić; Jasmina Brborić; Olivera Čudina Journal: RSC Med Chem Date: 2020-02-14
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Authors: Mohamed El-Sherbiny; Rehab M El-Sayed; Mohamed A Helal; Afaf T Ibrahiem; Hoda S Elmahdi; Mohamed Ahmed Eladl; Shymaa E Bilay; Asma M Alshahrani; Mona K Tawfik; Ziad E Hamed; Amany O Mohamed; Sawsan A Zaitone Journal: Molecules Date: 2021-11-13 Impact factor: 4.411
Authors: Daiana K Frade Silva; Sâmia S Duarte; Thaís M H Lisboa; Rafael C Ferreira; Ana Luíza de O Lopes; Deyse C M Carvalho; Sandra Rodrigues-Mascarenhas; Patricia Mirella da Silva; Miguel A S Pinheiro Segundo; Ricardo O de Moura; Karina C P Medeiros; Marianna V Sobral Journal: Molecules Date: 2019-12-20 Impact factor: 4.411