Thiosemicarbazones derived from acetylpyrazines were prepared by condensing an acetylpyrazine or a ring-substituted acetylpyrazine with thiosemicarbazide. Using the same procedure, N, N-dimethylthiosemicarbazones were synthesized from acetylpyrazines and N, N-dimethylthiosemicarbazide. A total of 20 compounds (16 novel) were chemically characterized and then tested for antifungal effects on eight strains of fungi and also for antitumor activity against SK-N-MC neuroepithelioma cells. The most effective compound identified in terms of both antifungal and antitumor activity was N, N-dimethyl-2-(1-pyrazin-2-ylethylidene)hydrazinecarbothioamide (5a). The mechanism of action of this and its related thiosemicarbazones was due, at least in part, to its ability to act as a tridentate ligand that binds metal ions. This was deduced from preparation of the related thiosemicarbazones [acetophenone thiosemicarbazone (6) and acetophenone N, N-dimethylthiosemicarbazone (7)] that do not possess a coordinating ring-N, which plays a vital role in metal ion chelation. Furthermore, 5a and several other thiosemicarbazones that showed high antiproliferative activity were demonstrated to have marked iron (Fe) chelation efficacy. In fact, these agents were highly effective at mobilizing (59)Fe from prelabeled SK-N-MC cells and preventing (59)Fe uptake from the serum Fe transport protein, transferrin. In contrast, compounds 6 and 7 that do not possess a tridentate metal-binding site showed little activity. Further studies examining ascorbate oxidation demonstrated that the Fe complexes of the most effective compounds were redox-inactive. Thus, in contrast to other thiosemicarbazones with potent antiproliferative activity, Fe chelation and mobilization rather than free radical generation played a significant role in the cytotoxic effects of the current ligands.

中文翻译：

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具有抗真菌和抗肿瘤作用的硫代半脲酮的鉴定和表征：细胞铁螯合介导细胞毒性活性。

通过将乙酰基吡嗪或环取代的乙酰基吡嗪与硫代氨基脲缩合来制备衍生自乙酰基吡嗪的硫代氨基脲。使用相同的方法，由乙酰基吡嗪和N，N-二甲基硫代氨基脲合成N，N-二甲基硫代氨基脲。对总共20种化合物（16种新化合物）进行了化学表征，然后测试了其对八种真菌的抗真菌作用以及对SK-N-MC神经上皮瘤细胞的抗肿瘤活性。就抗真菌和抗肿瘤活性而言，鉴定出的最有效的化合物是N，N-二甲基-2-（1-吡嗪-2-基亚乙基）肼基碳硫磺酰胺（5a）。该化合物及其相关的硫代半氨基甲酮的作用机理至少部分是由于其充当结合金属离子的三齿配体的能力。这是从不具有配位环-N的相关硫代氨基甲磺酮[苯乙酮硫代半碳酮（6）和苯乙酮N，N-二甲基硫代半碳酮（7）]的制备中推论得出的，该配位环N在金属离子螯合中起着至关重要的作用。此外，已证明具有高抗增殖活性的5a和其他几种硫代半脲具有明显的铁（Fe）螯合功效。实际上，这些试剂在从预先标记的SK-N-MC细胞中动员（59）Fe并防止血清Fe转运蛋白转铁蛋白摄取（59）Fe方面非常有效。相反，不具有三齿金属结合位点的化合物6和7几乎没有活性。检查抗坏血酸氧化的进一步研究表明，最有效的化合物的Fe络合物是氧化还原惰性的。因此，