The sodium valproate has been largely used as an anti-epilepsy drug and, recently, as a putative drug in cancer therapy. However, the treatment with sodium valproate has some adverse effects. In this sense, more effective and secure complexes than sodium valproate should be explored in searching for new active drugs. This study aims to evaluate the cytotoxicity of sodium valproate, mixed ternary mononuclear Cu(II) complexes based on valproate acid (VA) with 1,10-phenanthroline (Phen) or 2,2’- bipyridine (Bipy) ligands - [Cu₂(Valp)₄], [Cu(Valp)₂Phen] and [Cu(Valp)₂Bipy] - in yeast Saccharomyces cerevisiae, proficient or deficient in different repair pathways, such as base excision repair (BER), nucleotide excision repair (NER), translesion synthesis (TLS), DNA postreplication repair (PRR), homologous recombination (HR) and non-homologous end-joining (NHEJ). The results indicated that the Cu(II) complexes have higher cytotoxicity than sodium valproate in the following order: [Cu(Valp)₂Phen] > [Cu(Valp)₂Bipy] > [Cu₂(Valp)₄] > sodium valproate. The treatment with Cu(II) complexes and sodium valproate induced mutations in S. cerevisiae. The data indicated that yeast strains deficient in BER (Ogg1p), NER (complex Rad1p-Rad10p) or TLS (Rev1p, Rev3p and Rad30p) proteins are associated with increased sensitivity to sodium valproate. The BER mutants (ogg1Δ, apn1Δ, rad27Δ, ntg1Δ and ntg2Δ) showed increased sensitivity to Cu(II) complexes. DNA damage induced by the complexes requires proteins from NER (Rad1p and Rad10p), TLS (Rev1p, Rev3p and Rad30p), PRR (Rad6 and Rad18p) and HR (Rad52p and Rad50p) for efficient repair. Therefore, Cu(II) complexes display enhanced cytotoxicity when compared to the sodium valproate and induce distinct DNA lesions, indicating a potential application as cytotoxic agents.

丙戊酸钠已被广泛用作抗癫痫药物，并且最近被用作癌症治疗中的推定药物。然而，用丙戊酸钠治疗有一些副作用。从这个意义上说，在寻找新的活性药物时应该探索比丙戊酸钠更有效和更安全的复合物。本研究旨在评估丙戊酸钠、基于丙戊酸 (VA) 与 1,10-菲咯啉 (Phen) 或 2,2'- 联吡啶 (Bipy) 配体的混合三元单核 Cu(II) 复合物的细胞毒性 - [Cu ₂ (Valp) ₄ ]、[Cu(Valp) ₂ Phen] 和 [Cu(Valp) ₂ Bipy] - 在酵母酿酒酵母中, 精通或缺乏不同修复途径，如碱基切除修复 (BER)、核苷酸切除修复 (NER)、跨损伤合成 (TLS)、DNA 复制后修复 (PRR)、同源重组 (HR) 和非同源末端连接(NHEJ)。结果表明，Cu(II)配合物比丙戊酸钠具有更高的细胞毒性，顺序为：[Cu(Valp) ₂ Phen] > [Cu(Valp) ₂ Bipy] > [Cu ₂ (Valp) ₄ ] >丙戊酸钠. Cu(II)配合物和丙戊酸钠处理诱导酿酒酵母突变. 数据表明，缺乏 BER（Ogg1p）、NER（复合 Rad1p-Rad10p）或 TLS（Rev1p、Rev3p 和 Rad30p）蛋白的酵母菌株与对丙戊酸钠的敏感性增加有关。BER 突变体（ogg1Δ、apn1Δ、rad27Δ、ntg1Δ和ntg2Δ）对 Cu(II) 复合物的敏感性增加。复合物引起的 DNA 损伤需要来自 NER（Rad1p 和 Rad10p）、TLS（Rev1p、Rev3p 和 Rad30p）、PRR（Rad6 和 Rad18p）和 HR（Rad52p 和 Rad50p）的蛋白质才能有效修复。因此，与丙戊酸钠相比，Cu(II) 复合物显示出增强的细胞毒性并诱导明显的 DNA 损伤，表明作为细胞毒性剂的潜在应用。