遗传毒性
细胞毒性
体内
药理学
彗星试验
毒性
化学
MTT法
微核试验
生物信息学
体外
广告
微核
DNA损伤
生物
生物化学
DNA
生物技术
有机化学
基因
作者
Kimberly Brito Tecchio,Fernanda de Moura Alves,Janaina Domingas Alves,Camila de Souza Barbosa,Mariana A. R. Salgado,Vanessa Jaqueline da Silva Vieira dos Santos,Fernando de Pilla Varotti,Paulo Henrique Almeida Campos-Júnior,Gustavo Henrique Ribeiro Viana,Fábio Vieira dos Santos
标识
DOI:10.1016/j.mrgentox.2024.503808
摘要
The aim of this study was to evaluate the in vitro cytotoxic, genotoxic, and mutagenic potential and to determine the in silico ADME parameters of two synthetic β-carboline alkaloids developed as prototypes of antitumor agents (NQBio-06 and NQBio-21). Additionally, acute toxicity of the compounds was evaluated in mice. The results from the MTT assay showed that NQBio-06 presented higher cytotoxicity in the ovarian cancer cell line TOV-21 G (IC50 = 2.5 µM, selectivity index = 23.7). NQBio-21 presented an IC50 of 6.9 µM and a selectivity index of 14.5 against MDA-MB-231 breast cancer cells. Comet assay results showed that NQBio-06 did not induce chromosomal breaks in vitro, but NQBio-21 was genotoxic with and without metabolic activation (S9 fraction). Micronucleus assay showed that both compounds were mutagenic. In addition, metabolic activation enhanced this effect in vitro. The in silico predictions showed that the compounds met the criteria set by Lipinski's rules, had strong prediction for intestinal absorption, and were possible substrates for P-glycoprotein. The in vivo results demonstrated that both the compounds exhibited low acute toxicity. These results suggest that the mechanisms underlying the cytotoxicity of NQBio-06 and NQBio-21 are related to DNA damage induction and that the use of S9 enhanced these effects. In vivo analysis showed signs of toxicity after a single administration of the compounds in mice. These findings highlight the potential of β-carboline compounds as sources for the development of new anticancer chemotherapeutic agents.
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