La Manna Sara, Florio Daniele, Platts James A, Gabano Elisabetta, Ravera Mauro, Marasco Daniela
Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy.
IRCCS SYNLAB SDN, Via G. Ferraris 144, 80146, Naples, Italy.
Dalton Trans. 2025 Jul 1;54(26):10416-10425. doi: 10.1039/d5dt00691k.
Among novel metallodrugs, Pt(IV) complexes have been receiving increasing attention as alternatives to Pt(II) analogues since they exhibit superior kinetic inertness and, hence, fewer undesirable reactions. Pt(IV) complexes have been designed as prodrugs with mechanisms of action finely tuned by properties of the axial ligands. In this context, the insertion of known bioactive molecules as axial ligands to generate multi-target drugs (MTDs) is considered a valuable drug design strategy because of the possible synergistic effects between the metal centre and the organic moiety. By employing the repurposing of drugs in different diseases, in this study, the Pt(IV) complex (-6-44)-acetatodiamminedichlorido(4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato)platinum(IV) was investigated for its ability to modulate the self-aggregation process of the amyloid peptide Aβ. Specifically, the complex features 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato (rhein) as a ligand that is a natural aromatic molecule already known as a discrete inhibitor of amyloid aggregation. Herein, several biophysical and microscopic assays, such as thioflavin T (ThT) fluorescence, dynamic light scattering (DLS) and scanning electron (SEM) and confocal microscopy, indicated that the Pt(IV) complex can inhibit and disassemble Aβ aggregation to a greater extent with respect to rhein alone. This effect is likely due to the formation of π-π interactions between the rhein moiety and the side chains of the Aβ peptide. This experimental evidence was confirmed by molecular docking studies of monomeric and tetrameric Aβ. Overall, the data support the application of Pt(IV) complexes as innovative neurotherapeutics.
在新型金属药物中，Pt(IV)配合物作为Pt(II)类似物的替代品受到越来越多的关注，因为它们表现出优异的动力学惰性，因此不良反应较少。Pt(IV)配合物已被设计为前药，其作用机制可通过轴向配体的性质进行精细调节。在这种情况下，插入已知的生物活性分子作为轴向配体以生成多靶点药物（MTDs）被认为是一种有价值的药物设计策略，因为金属中心和有机部分之间可能存在协同效应。通过采用在不同疾病中重新利用药物的方法，在本研究中，研究了Pt(IV)配合物（-6-44）-乙酸二氨二氯（4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羧基）铂（IV）调节淀粉样肽Aβ自聚集过程的能力。具体而言，该配合物的特征是4,5-二羟基-9,10-二氧代-9,10-二氢蒽-2-羧基（大黄酸）作为配体，它是一种天然芳香分子，已知是淀粉样聚集的离散抑制剂。在此，几种生物物理和显微镜检测，如硫黄素T（ThT）荧光、动态光散射（DLS）、扫描电子（SEM）和共聚焦显微镜，表明Pt(IV)配合物相对于单独的大黄酸可以在更大程度上抑制和分解Aβ聚集。这种效应可能是由于大黄酸部分与Aβ肽侧链之间形成了π-π相互作用。单体和四聚体Aβ的分子对接研究证实了这一实验证据。总体而言，数据支持将Pt(IV)配合物用作创新的神经治疗药物。
