Abstract Triapine, the most studied α-N-heterocyclic thiosemicarbazone, revealed potent activity against advanced leukemia, but was ineffective against a variety of solid tumors. Moreover, methemoglobinemia, which is a side effect of triapine administration, may limits all clinical application. To enhance anticancer activity and reduce side effects, we applied an isosteric replacement of sulfur to selenium atom was performed by synthesis and characterization of selenium triapine analog, 3-aminopyridine-2-carboxaldehyde selenosemicarbazone (selenotriapine). Compared to triapine, selenotriapine revealed superior pro-apoptotic activity with activation of intrinsic apoptotic pathway in both human monocytic leukemia (THP-1) and mammary adenocarcinoma (MCF-7) cell lines. For MCF-7 2-D cultures, selenotriapine induced notable increase in mitochondrial superoxide radical generation and dissipation of mitochondrial transmembrane potential. A significant delay in growth of MCF-7 spheroids (3-D culture) was accompanied by phenotypic stem cell reprogramming (Oct-4 expression). Additionally, selenotriapine demonstrated a very low toxicity profile as compared to triapine, confirmed over alleviated extent of methemoglobin formation and higher IC50 value in brine shrimp cytotoxicity assay.

中文翻译：

---

硒氮平是研究最多的缩氨基硫脲的等排体，具有显着的促凋亡活性、低毒性和挑战 3-D 乳腺癌肿瘤表型重编程的能力

摘要 Triapine 是研究最多的 α-N-杂环氨基硫脲，显示出对晚期白血病的有效活性，但对多种实体瘤无效。此外，高铁血红蛋白血症是曲阿平给药的副作用，可能会限制所有临床应用。为了增强抗癌活性并减少副作用，我们通过合成和表征硒三氮平类似物，3-氨基吡啶-2-羧基硒酮（selenotriapine），将硫等排置换为硒原子。与 triapine 相比，selenotriapine 在人单核细胞白血病 (THP-1) 和乳腺腺癌 (MCF-7) 细胞系中显示出优越的促凋亡活性，激活内在凋亡途径。对于 MCF-7 2-D 培养物，硒代曲平诱导线粒体超氧化物自由基生成和线粒体跨膜电位耗散的显着增加。MCF-7 球体（3-D 培养）生长的显着延迟伴随着表型干细胞重编程（Oct-4 表达）。此外，与三氮平相比，硒氮平表现出非常低的毒性特征，证实了在盐水虾细胞毒性测定中高铁血红蛋白形成的程度减轻和更高的 IC50 值。