Mizuno Cassia Suemi, Ampomaah Winnifred, Mendonça Fernanda Ribeiro, Andrade Gabriela Carvalho, Silva Ariel Maria Nazaré da, Goulart Mirian Oliveira, Santos Raquel Alves Dos
Department of Pharmaceutical Sciences, University of New England - College of Pharmacy, Portland, ME, USA.
Universidade de Franca, Franca, SP, Brazil.
Genet Mol Biol. 2017 Jul-Sep;40(3):656-664. doi: 10.1590/1678-4685-GMB-2016-0214. Epub 2017 Jul 10.
The cytotoxicity and genotoxicity of the stilbenes (E)-methyl-4-(3-5-dimethoxystyryl)benzoate (ester), (E)-4-(3-5-dimethoxystyryl)aniline (amino), (Z)-1,3-dimethoxy-5-(4-methoxystyryl)benzene (cis-TMS) and (E)-1,3-dimethoxy-5-(4-methoxystyryl)benzene (trans-TMS) were investigated in this work. Structural modifications of resveratrol, a naturally occurring stilbene, have been previously performed, including the replacement of hydroxyl by different functional groups. Such modifications resulted in significant improvement of target-specific effects on cell death and antiproliferative responses. The parameters were evaluated using XTT assay, clonogenic survival assay and the cytokinesis-block micronucleus assay in CHO-K1 and HepG2 cell lines. The results showed that cis-TMS is approximately 250-fold more cytotoxic than the amino and ester, and 128-fold more cytotoxic than trans-TMS. When genotoxicity was evaluated, only the trans-TMS did not significantly increase the frequency of micronucleus (MN). While the cis-TMS induced a mean of 5.2 and 5.9 MN/100 cells at 0.5 μM in CHO-K1 and HepG2, respectively, the amino and ester induced 3.1 and 3.6 MN/100 cells at 10 μM in CHO-K1, respectively, and 3.5 and 3.8 in HepG2. Trans-TMS is genotoxic only in HepG2 cells. Based on these results, the cis-TMS was the most cytotoxic and genotoxic compound in both cell lines.
本研究考察了二苯乙烯类化合物（E）-4-（3,5-二甲氧基苯乙烯基）苯甲酸甲酯（酯类）、（E）-4-（3,5-二甲氧基苯乙烯基）苯胺（氨基类）、（Z）-1,3-二甲氧基-5-（4-甲氧基苯乙烯基）苯（顺式-TMS）和（E）-1,3-二甲氧基-5-（4-甲氧基苯乙烯基）苯（反式-TMS）的细胞毒性和遗传毒性。白藜芦醇是一种天然存在的二苯乙烯，之前已对其进行结构修饰，包括用不同官能团取代羟基。这些修饰显著改善了对细胞死亡和抗增殖反应的靶向特异性作用。使用XTT法、克隆形成存活试验和胞质分裂阻滞微核试验在CHO-K1和HepG2细胞系中评估各项参数。结果表明，顺式-TMS的细胞毒性比氨基类和酯类化合物高约250倍，比反式-TMS高128倍。在评估遗传毒性时，只有反式-TMS没有显著增加微核（MN）频率。顺式-TMS在CHO-K1和HepG2细胞中，0.5 μM时分别诱导平均5.2和5.9个MN/100细胞，氨基类和酯类化合物在CHO-K1细胞中10 μM时分别诱导3.1和3.6个MN/100细胞，在HepG2细胞中分别诱导3.5和3.8个MN/100细胞。反式-TMS仅在HepG2细胞中具有遗传毒性。基于这些结果，顺式-TMS是两种细胞系中细胞毒性和遗传毒性最强的化合物。
