Mangueira Vivianne Mendes, Batista Tatianne Mota, Brito Monalisa Taveira, Sousa Tatyanna Kelvia Gomes de, Cruz Ryldene Marques Duarte da, Abrantes Renata Albuquerque de, Veras Robson Cavalcanti, Medeiros Isac Almeida de, Medeiros Karina Karla de Paula, Pereira Ana Ligia da Costa, Serafim Vanessa de Lima, Moura Ricardo Olímpio de, Sobral Marianna Vieira
Programa de Pós Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, 58051-970 João Pessoa, Paraíba, Brazil, Brazil.
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.
Biomed Pharmacother. 2017 Jun;90:253-261. doi: 10.1016/j.biopha.2017.03.049. Epub 2017 Mar 30.
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).
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.
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 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.
ACS-AZ10 has potent antitumor activity in vivo along with low toxicity.
包括安吖啶在内的吖啶衍生物具有抗肿瘤活性。然而，副作用、耐药性的产生以及它们较低的生物利用度限制了其应用。在此，我们描述了一种新的安吖啶类似物N'-(2-氯-6-甲氧基-吖啶-9-基)-2-氰基-3-(4-二甲基氨基苯基)-吖啶酰肼(ACS-AZ10)的合成，并评估了其毒性和抗肿瘤活性。
该化合物通过线性途径获得，其中通过6,9-二氯-3-甲氧基-吖啶与2-氰基-乙酰肼偶联，然后与相应的醛缩合得到ASC-Az中间体。使用急性毒性和微核试验在小鼠中评估ACS-AZ10的毒性。在治疗九天后，使用艾氏腹水癌模型研究ACS-AZ10(7.5、15或30mg/kg，腹腔注射)的抗肿瘤活性和毒性。还评估了细胞周期和血管生成。
以令人满意的产率获得了ASC-AZ10，并通过光谱和光谱技术确认了其结构。在急性毒性研究中，ACS-AZ10(2000mg/kg，腹腔注射)对中枢神经系统产生短暂的抑制作用。LD约为2500mg/kg。考虑到肿瘤重量和体积、细胞活力以及艾氏细胞总数，ACS-AZ10(15或30mg/kg)显示出显著的抗肿瘤活性。ACS-AZ10(7.5mg/kg)诱导亚G1峰增加，提示细胞凋亡。在15mg/kg时，ACS-AZ10诱导细胞周期停滞在G2/M期，并降低G0/G1和S期细胞的百分比，提示有丝分裂前阻滞。ACS-AZ10降低了微血管密度，表明具有抗血管生成作用。观察到较弱的血液学、生化和组织病理学毒性。该化合物在微核试验中未显示出遗传毒性。
ACS-AZ10在体内具有强大的抗肿瘤活性且毒性较低。
