Laboratório de Síntese e Interações Bioinorgânicas (SibLab), Department of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Chair of Medicinal and Bioinorganic Chemistry, Department of Chemistry, Technical University of Munich, Garching b. Munich, Germany.
RdM Lab - Biotechnology Applied to Pathogens Research Group, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Brazil.
J Inorg Biochem. 2023 Oct;247:112346. doi: 10.1016/j.jinorgbio.2023.112346. Epub 2023 Jul 29.
The limited chemical stability of gold(III)-based compounds in physiological environment has been a challenge in drug discovery, and organometallic chemistry might provide the solution to overcome this issue. In this work, four novel cationic organogold(III)-dithiocarbamate complexes of general structure [(C^N)AuDTC]PF (C1a - C4a, DTC = dithiocarbamate, L1 - L4, C^N = 2-anilinopyridine) are presented, and compared to their coordination gold(III)-dithiocarbamate analogues [AuDTCCl] (C1b - C4b), as potential anti-cancer and anti-leishmanial drugs. Most of the complexes effectively inhibited cancer cell growth, notably C3a presented anti-proliferative effect in the nanomolar range against breast cancer (MCF-7 and MDA-MB-231 cells with moderate selectivity. Pro-apoptotic studies on treated MCF-7 cells showed a high population of cells in early apoptosis. Reactivity studies of C3a towards model thiols (N-acetyl-L-cysteine) refer to a possible mode of action involving bonding between the organogold(III)-core and the thiolate. In the scope of neglected diseases, gold complexes are emerging as promising therapeutic alternatives against leishmaniasis. In this regard, all gold(III)-dithiocarbamate complexes presented anti-leishmanial activity against at least one Leishmania species. Complexes C1a, C4a, C1b, C4b were active against all tested parasites with IC values varying between 0.12 and 42 μM, and, overall, organometallic compounds presented more intriguing inhibition profiles. For C4a selectivity over 500-fold for L. braziliensis; even higher than the reference anti-leishmanial drug amphotericin B. Overall, our findings revealed that the organogold(III) moiety significantly amplified the anti-cancer and anti-leishmanial effects with respect to the coordination analogues; thus, showing the great potential of organometallic chemistry in metallodrug-based chemotherapy for cancer and leishmaniasis.
在生理环境中，金（III）基化合物的化学稳定性有限，这一直是药物发现中的一个挑战，而有机金属化学可能提供了解决这个问题的方法。在这项工作中，我们提出了四种新型的阳离子有机金（III）-二硫代氨基甲酸盐配合物，其通式为[(C^N)AuDTC]PF（C1a - C4a，DTC = 二硫代氨基甲酸盐，L1 - L4，C^N = 2- 苯胺基吡啶），并将其与它们的配位金（III）-二硫代氨基甲酸盐类似物[AuDTCCl]（C1b - C4b）进行了比较，作为潜在的抗癌和抗利什曼病药物。大多数配合物有效地抑制了癌细胞的生长，特别是 C3a 对乳腺癌（MCF-7 和 MDA-MB-231 细胞）具有中等选择性的纳米级抗增殖作用。对经处理的 MCF-7 细胞进行的促凋亡研究表明，早期凋亡的细胞数量较多。C3a 与模型硫醇（N-乙酰-L-半胱氨酸）的反应性研究表明，一种可能的作用模式涉及有机金（III）-核与硫醇化物之间的键合。在被忽视的疾病范围内，金配合物作为治疗利什曼病的有前途的治疗替代物而崭露头角。在这方面，所有金（III）-二硫代氨基甲酸盐配合物对至少一种利什曼原虫都具有抗利什曼病活性。配合物 C1a、C4a、C1b、C4b 对所有测试的寄生虫均具有活性，IC 值在 0.12 和 42 μM 之间变化，总的来说，有机金属化合物呈现出更有趣的抑制谱。对于 C4a，对 L. braziliensis 的选择性超过 500 倍；甚至高于参考抗利什曼病药物两性霉素 B。总的来说，我们的发现表明，与配位类似物相比，有机金（III）部分显著增强了抗癌和抗利什曼病的效果；因此，展示了有机金属化学在基于金属药物的癌症和利什曼病化疗中的巨大潜力。
