Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The platinum complexes are unusual among modern pharmaceuticals in that they are inorganic compounds possessing a metallic element whereas most drugs are purely organic. Platinum-based antineoplastic agents are sometimes described as “alkylating agents”, which is incorrect as they do not contain an alkyl group; “platinating agents” would be a more technically correct term. The success of the prototypic cisplatin (Figure 5.32) is due to a number of reasons including a broad spectrum of antitumor activity against drug-resistant as well as drug-sensitive tumors, and activity against slow-growing and rapidly growing tumors, and both primary solid and disseminated tumors. In animal models it is active against viral- and chemical-induced tumors and transplantable tumors, and shows no strain or species specificity, which is why it is widely used in veterinary medicine. Structures of cisplatin, carboplatin (ParaplatinTM), and oxaliplatin (EloxatinTM).
Antitumor Active Trans-Platinum Compounds
Astrid Sigel, Helmut Sigel in Metal Ions in Biological Systems, 2004
Some general conclusion can be drawn from the chemical behaviour of trans-platinum complexes as compared to cis-platinum species. Trans-platinum complexes will react faster with nucleophiles in the dichloro and chloro-aqua forms, yet not in the diaqua form. In the monoadducts with DNA the residual chloride will direct the substitution by an incoming nucleophile (such as thiourea and glutathione) within the pair of CI and NH3trans-ligands in the case of cisplatin and within the pair of Cl and DNA trans-ligands in the case of transplatin (Scheme 5). Therefore repair of trans-DDP monoadducts could occur simply by a chemical pathway whereas repair of cis-DDP monoadducts might require an enzymatic pathway. Finally, because of the trans disposition of the leaving ligands, trans-platinum complexes will give chelation reaction less readily than cis-platinum complexes (formation of 1,2-intrastrand cross-link is greatly hindered [83] in favor of 1,3 or larger intrastrand cross-links).
Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Malignancies
II-Jin Kim in Cancer Genetics and Genomics for Personalized Medicine, 2017
Cisplatin can be administered intravenously (IV) or through intrapleural/intraperitoneal (IP) injection. Since platinum is insoluble in aqueous solution, it is administered in a chelated form (cis-[Pt(NH3)2(Cl)2]). Once in the body, one of its chloride ligands is slowly displaced by water (an aqua ligand) in a process termed aquation. The aqua ligand in the resulting [Pt(NH3)2(H2O)(Cl)]+ is itself easily displaced, allowing the platinum atom to bind to nitrogenous base of DNA (guanine is preferred). Subsequent to formation of Pt(NH3)2(Cl)(guanine-DNA)]+, cross linking can occur via displacement of Cisplatin’s second chloride ligand, typically by another guanine (Trzaksa, 2005).
A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Robert Czarnomysy, Arkadiusz Surażyński, Anna Muszynska, Agnieszka Gornowicz, Anna Bielawska, Krzysztof Bielawski
Of the non-classical platinum compounds, multi-nucleic complexes appear to have the highest potential for high cytotoxicity and maintenance of platinum activity in resistant cell lines. Thanks to the use of ligands within the coordinated platinum zone, compounds with differentiated functions and geometry were obtained25. Following this trend, our team synthesised a group of pyrazole-platinum(II) complexes. The electronic properties of pyrazole ligands offer metal centers for late transition metals that are quite electrophilic to allow coordination to biological molecules26. Interestingly, pyrazole derivatives are characterised by a wide spectrum of biological activity: anti-tumor, anti-viral, anti-microbial, and anti-inflammatory. The considerable amount of research has reported that pyrazole-based heterocyclic show promising activity against cancer cell lines, including human breast cancer cell lines26. The advantage of these derivatives is the ease of complexing with platinum, which may result in an increase in its performance17.
Synergic highly effective photothermal-chemotherapy with platinum prodrug linked melanin-like nanoparticles
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Chengwei Zhang, Xiaozhi Zhao, Hongqian Guo
Cisplatin is a kind of common chemotherapy drugs based on platinum group elements. Cisplatin has been widely used in tumour treatment, including testicular cancer, ovarian cancer, breast cancer, bladder cancer and prostate cancer [1–3]. Together with the analogues carboplatin and oxaliplatin, cisplatin is applied in the first-line treatment of malignant tumours. The anti-tumour effect of platinum-based drugs mainly depends on binding with DNA to form DNA adducts [4,5]. Although the efficacy of platinum compounds in anti-tumour activity has been universally recognized, their application is still facing some restrictions, such as some serious side effects due to binding to the essential amino acids in the plasma. Several novel platinum compounds have also been synthesized to further promote the anti-tumour activities [6,7]. The platinum prodrug Pt(IV) shows a number of advantages over the conventional Pt(II) compounds. The pharmacological properties of platinum are also slightly modified after Pt(II) oxidation, such as lipophilicity, dynamic stability and reduction potential [8]. As a prodrug, the Pt(IV) compound is required to be reduced in the surrounding environment first by bio-reductive agents such as ascorbic acid (AsA) or glutathione (GSH) before releasing the cytotoxic Pt(II) fragments [9,10].
A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Wenjing Liu, Min He, Yongjun Li, Zhiyun Peng, Guangcheng Wang
Multi-target drugs have attracted more and more attention. To obtain compounds with high cytotoxicity, the pharmacophore binding to a single compound molecule has become the design method of new anti-tumour drugs107–109. Platinum compounds are widely used in clinical practice but have serious toxic and side effects, such as nephrotoxicity, neurotoxicity, and myelosuppression110. To overcome these shortcomings, researchers have designed novel platinum-based complexes that combine platinum with other pharmacophore groups to reduce toxic side effects. Prompted by this idea, the researcher's combination of the active groups of microtubule inhibitors with cytotoxic DNA-damaging platinum compounds to obtain complexes can also be considered as an effective strategy to target tubulin and DNA, at least theoretically, to enhance the antitumor activity of platinum drugs and overcome their side effects.