Wittmann Christopher, Besleaga Iuliana, Mahmoudi Soheil, Palamarciuc Oleg, Balan-Porcarasu Mihaela, Dascalu Mihaela, Shova Sergiu, Cazacu Maria, Kiricsi Mónika, Igaz Nóra, Dömötör Orsolya, Enyedy Eva A, Dvoranová Dana, Rapta Peter, Arion Vladimir B
University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, 1090 Vienna, Austria.
University of Vienna, Vienna Doctoral School in Chemistry (DoSChem), Währinger Strasse 42, 1090 Vienna, Austria.
Dalton Trans. 2025 May 13;54(19):7882-7898. doi: 10.1039/d5dt00314h.
The incorporation of non-native chemical elements, such as silicon, into drug molecules has gained significant attention as a strategy to broaden the chemical space in medicinal chemistry and develop novel drug candidates. Traditionally, research has focused on the isosteric replacement of a carbon atom with silicon ("silicon switch") in known drug structures or the attachment of a trimethylsilyl (TMS) group to biologically active scaffolds. In this study, a TMS-substituted indoloquinoline-based Schiff base (HLTMS) and its corresponding metal complexes, (1) and (2), were synthesized and comprehensively characterized using elemental analysis, spectroscopic techniques (IR, UV-vis, H and C NMR for HLTMS and 2), ESI mass spectrometry and single-crystal X-ray diffraction (SC-XRD) for 1 and electron diffraction (ED) for 2. The attachment of the TMS group enhanced the lipophilicity of HLTMS, while complex formation with Cu(II) substantially improved the antiproliferative activity. Exploitation of their intrinsic fluorescence to investigate cellular uptake and intracellular localization in cancer cells was impeded by limited solubility. Both HLTMS and 2 were found to generate reactive oxygen species under cell-free conditions in accord with their redox activity established by cyclic voltammetry. The photochemical activity of the indolo[2,3-]quinoline-based proligand HLTMS and its complexes 1 and 2 has been disclosed. The compounds exhibited significant toxicity on various human cancer cells and disrupted the mitochondrial membrane potential, suggesting the contribution of mitochondrial dysfunction, triggered by HLTMS and its metal complexes, to their toxic effects. These findings highlight the potential of TMS-substituted Schiff bases as promising anticancer drug candidates.
将非天然化学元素（如硅）引入药物分子，作为拓宽药物化学中化学空间并开发新型候选药物的一种策略，已受到广泛关注。传统上，研究主要集中在已知药物结构中用硅原子进行等排取代碳原子（“硅开关”），或在生物活性支架上连接三甲基硅基（TMS）基团。在本研究中，合成了一种TMS取代的基于吲哚喹啉的席夫碱（HLTMS）及其相应的金属配合物（1）和（2），并使用元素分析、光谱技术（HLTMS和2的红外光谱、紫外可见光谱、氢谱和碳谱）、ESI质谱以及1的单晶X射线衍射（SC-XRD）和2的电子衍射（ED）对其进行了全面表征。TMS基团的连接增强了HLTMS的亲脂性，而与Cu(II)形成配合物则显著提高了其抗增殖活性。由于溶解度有限，利用其固有荧光来研究癌细胞中的细胞摄取和细胞内定位受到阻碍。发现HLTMS和2在无细胞条件下均能产生活性氧，这与其通过循环伏安法确定的氧化还原活性一致。已揭示了基于吲哚[2,3 -]喹啉的前体配体HLTMS及其配合物1和2的光化学活性。这些化合物对多种人类癌细胞表现出显著毒性，并破坏线粒体膜电位，表明HLTMS及其金属配合物引发的线粒体功能障碍对其毒性作用有贡献。这些发现突出了TMS取代的席夫碱作为有前景的抗癌候选药物的潜力。
