目前大多数治疗癌症的细胞毒素均缺乏选择性，因此会引起严重的副作用。这种情况激发了我们研发新型具有更强亲和力的抗增生药物，重点关注新型含碲化合物（硫代半脲、二硫化物、硒呋咱、硫氰酸盐和硒氰酸盐）以及特别是硒衍生物，因为这种化合物可以作为前药，在肿瘤细胞上释放基于硒的反应性物种。具有潜力和选择性的药效团是由硒氰基乙基片段与p-苯二胺残基相连组成的，其中第二个氨基基团的性质（自由、Boc保护、烯胺保护）提供了广泛的抗增生活性，范围从低微摩尔到纳摩尔不等。优化后的结构通过肽键与生物素（维生素B7）结合，并具有选择性地作用于恶性细胞，因为其受体在许多癌细胞中过度表达。这种生物素化衍生物表现出非常强的抗增生活性，在大多数测试的癌细胞中实现低纳摩尔范围的GI50值，而且具有杰出的选择性，在人类成纤维细胞中的GI50值>100μM。对于生物素化硒氰酸盐的抑制模式的机理研究（Annexin-V试验）显示，与对照实验相比，凋亡细胞数量显著增加；此外，流式细胞仪分析和荧光显微镜检测显示线粒体膜极性发生改变，证实目标细胞经历了凋亡细胞死亡过程。在凋亡事件之前，通过无标记活细胞成像对SW1573细胞观察到细胞增殖受到抑制。多药耐药细胞系对生物素化硒氰酸盐的敏感性降低，可能是由于P-gp介导的外排。值得注意的是，通过联合应用P-gp抑制剂tariquidar，可以恢复抗增生水平，从而克服P-gp外流系统介导的多药耐药。 © 2023 Elsevier Inc. 保留所有权利。

Most of the currently available cytotoxic agents for tackling cancer are devoid of selectivity, thus causing severe side-effects. This situation stimulated us to develop new antiproliferative agents with enhanced affinity towards tumour cells. We focused our attention on novel chalcogen-containing compounds (thiosemicarbazones, disulfides, selenoureas, thio- and selenocyanates), and particularly on selenium derivatives, as it has been documented that this kind of compounds might act as prodrugs releasing selenium-based reactive species on tumour cells. Particularly interesting in terms of potency and selectivity was a pharmacophore comprised by a selenocyanato-alkyl fragment connected to a p-phenylenediamine residue, where the nature of the second amino moiety (free, Boc-protected, enamine-protected) provided a wide variety of antiproliferative activities, ranging from the low micromolar to the nanomolar values. The optimized structure was in turn conjugated through a peptide linkage with biotin (vitamin B7), a cellular growth promoter, whose receptor is overexpressed in numerous cancer cells; the purpose was to develop a selective vector towards malignant cells. Such biotinylated derivative behaved as a very strong antiproliferative agent, achieving GI50 values in the low nM range for most of the tested cancer cells; moreover, it was featured with an outstanding selectivity, with GI50 > 100 µM against human fibroblasts. Mechanistic studies on the mode of inhibition of the biotinylated selenocyanate revealed (Annexin-V assay) a remarkable increase in the number of apoptotic cells compared to the control experiment; moreover, depolarization of the mitochondrial membrane was detected by flow cytometry analysis, and with fluorescent microscopy, what supports the apoptotic cell death. Prior to the apoptotic events, cytostatic effects were observed against SW1573 cells using label-free cell-living imaging; therefore, tumour cell division was prevented. Multidrug resistant cell lines exhibited a reduced sensitivity towards the biotinylated selenocyanate, probably due to its P-gp-mediated efflux. Remarkably, antiproliferative levels could be restored by co-administration with tariquidar, a P-gp inhibitor; this approach can, therefore, overcome multidrug resistance mediated by the P-gp efflux system.Copyright © 2023 Elsevier Inc. All rights reserved.