More of a misunderstanding than a real mismatch? Platinum and its affinity for aqua, hydroxido, and oxido ligands

Lippert, Bernhard; Miguel, Pablo J. Sanz

doi:10.1016/j.ccr.2016.03.008

Cited by 42 publications

(20 citation statements)

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“…However, studies in recent years have shown that the copper transport protein CTR1 and organic cation transporters (OCTs) also play important roles in the transport of cisplatin. , Outside cells, cisplatin is not susceptible to hydrolysis due to the high concentration of chloride ions (approximately 100 mM) in blood. Once in cells, cisplatin undergoes slow hydrolysis to form the cationic monoaqua and/or diaqua complexes (Figure ) due to a much lower concentration of chloride ions (4–22 mM). − The monoaqua and diaqua complexes ([Pt(NH 3 ) 2 Cl(OH 2 )] + and [Pt(NH 3 ) 2 (OH 2 ) 2 ] 2+ are recognized as highly reactive hydrolysis products of cisplatin and can react more readily with various cellular targets …”

Section: Overview Of Cisplatinmentioning

confidence: 99%

Advances in Toxicological Research of the Anticancer Drug Cisplatin

Luo

Zhang

et al. 2019

Chem. Res. Toxicol.

304

184

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Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic due to its high efficacy and broad spectrum. The antineoplastic activity of cisplatin is mainly due to its ability to cross-link with DNA, thus blocking transcription and replication. Unfortunately, the clinical use of cisplatin is limited by its severe, dose-dependent toxic side effects. There are approximately 40 specific toxicities of cisplatin, among which nephrotoxicity is the most common one. Other common side effects include ototoxicity, neurotoxicity, gastrointestinal toxicity, hematological toxicity, cardiotoxicity, and hepatotoxicity. These side effects together reduce the life quality of patients and require lowering the dosage of the drug, even stopping administration, thus weakening the treatment effect. Few effective measures exist clinically against these side effects because the exact mechanisms of various side effects from cisplatin remain still unclear. Therefore, substantial effort has been made to explore the complicated biochemical processes involved in the toxicology of cisplatin, aiming to identify effective ways to reduce or eradicate its toxicity. This review summarizes and reviews the updated advances in the toxicological research of cisplatin. We anticipate to provide insights into the understanding of the mechanisms underlying the side effects of cisplatin and designing comprehensive therapeutic strategies involving cisplatin. OVERVIEW OF CISPLATIN1.1. Chemistry of Cisplatin. Cisplatin, chemically named cis-diamminedichloroplatinum (CDDP), was synthesized by M. Peyrone in 1844 for the first time. However, this compound did not gain much scientific attention until 1965. In this year, Rosenberg found that the electrolytic product of platinum electrodes can inhibit the growth of Escherichia coli and was later characterized to be CDDP. 1 After more than 10 years of bench and preclinic research as well as clinical trials, CDDP was approved by the FDA in 1978 for clinical use as a chemotherapeutic agent with the name cisplatin. Since then, cisplatin has been used to treat various human malignancies, including ovarian cancer, cervical cancer, testicular cancer, head and neck cancer, nonsmall cell lung cancer, and many other solid tumors. 2−4 Cisplatin is centered on a platinum atom which coordinates with two chlorine atoms and two ammonia groups to form a planar quadrilateral compound. The two chlorine atoms are on the same side (Figure 1). Initially, it was widely accepted that cisplatin enters cells by passive transport. However, studies in recent years have shown that the copper transport protein CTR1 and organic cation transporters (OCTs) also play important roles in the transport of cisplatin. 5,6 Outside cells, cisplatin is not susceptible to hydrolysis due to the high concentration of chloride ions (approximately 100 mM) in blood. Once in cells, cisplatin undergoes slow hydrolysis to form the cationic monoaqua and/or diaqua complexes (Figure 1) due to a

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Section: Overview Of Cisplatinmentioning

confidence: 99%

Advances in Toxicological Research of the Anticancer Drug Cisplatin

Luo

Zhang

et al. 2019

Chem. Res. Toxicol.

304

184

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“…Both compounds have three ligands capable of undergoing such reactions: H 2 O/OH − , 1MeU − , and NH 3 . There is ample structural evidence for the existence of μ‐OH, μ‐1MeU, and μ‐NH 2 bridges in Pt II coordination chemistry [4,20,38] . Scheme 5 summarizes the various possibilities relevant to 1 b and 1b’ .…”

Section: Resultsmentioning

confidence: 99%

“…There is ample structural evidence for the existence of μ-OH, μ-1MeU, and μ-NH 2 bridges in Pt II coordination chemistry. [4,20,38] Scheme 5 summarizes the various possibilities relevant to 1 b and 1b'. As to the μ-amido species, the non-equivalence of the two NH 3 ligands in 1 b and 1b' leads to four possible products, which are pairwise geometrical isomers (F, G; F', G') and at the same time are pairwise involved in acid-base equilibria (F, F'; G, G').…”

Section: H 2 O (4)mentioning

confidence: 99%

On the Heterogeneous Nature of Cisplatin‐1‐Methyluracil Complexes: Coexistence of Different Aggregation Modes and Partial Loss of NH₃ Ligands as Likely Explanation

et al. 2021

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The conversion of the 1 : 1-complex of Cisplatin with 1-methyluracil (1MeUH), cis-[Pt(NH 3) 2 (1MeU-N3)Cl] (1 a) to the aqua species cis-[Pt(NH 3) 2 (1MeU-N3)(OH 2)] + (1 b), achieved by reaction of 1 a with AgNO 3 in water, affords a mixture of compounds, the composition of which strongly depends on sample history. The complexity stems from variations in condensation patterns and partial loss of NH 3 ligands. In dilute aqueous solution, 1 a, and dinuclear compounds cis-[(NH 3) 2 (1MeU-N3)Pt(μ-OH)Pt(1MeU-N3)(NH 3) 2 ] + (3) as well as head-tail cis-[Pt 2 (NH 3) 4 (μ-1MeU-N3,O4) 2 ] 2 + (4) represent the major components. In addition, there are numerous other species present in minor quantities, which differ in metal nuclearity, stoichiometry, stereoisomerism, and Pt oxidation state, as revealed by a combination of 1 H NMR and ESI-MS spectroscopy. Their composition appears not to be the consequence of a unique and repeating coordination pattern of the 1MeU ligand in oligomers but rather the coexistence of distinctly different condensation patterns, which include μ-OH, μ-1MeU, and μ-NH 2 bridging and combinations thereof. Consequently, the products obtained should, in total, be defined as a heterogeneous mixture rather than a mixture of oligomers of different sizes. In addition, a N 2 complex, [Pt(NH 3)(1MeU)(N 2)] + appears to be formed in gas phase during the ESI-MS experiment. In the presence of Na + ions, multimers n of 1 a with n = 2, 3, 4 are formed that represent analogues of non-metalated uracil quartets found in tetrastranded RNA.

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“…Hydroxo‐bridged platinum(II) multimers can be also formed as revealed in several early studies . Complexes including PtO bonds were thoroughly reviewed in Lippert and Sanz Miguel . Except for aqua, oxo, and hydroxo complexes, there are reports (based on nuclear magnetic resonance studies) about cisplatin interaction with buffering media, which leads to a huge variety of complexes, such as for instance:…”

Section: Introductionmentioning

confidence: 99%

Cisplatin interacting with buffering media and cysteine: Molecular insight due to Raman microspectroscopy

Šišková

2019

J Raman Spectroscopy

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The solvation of cisplatin, [Pt(NH3)2Cl2], a widely used chemotherapeutical drug, regarded on molecular level in model media is often overlooked by researchers. It is, however, essential in several aspects. The solvation was monitored by using Raman scattering microspectroscopy. This technique being used for the first time enables us to focus the laser beam several micrometers above the dissolving crystals of cisplatin, allowing to monitor the process of cisplatin dissolution in situ. The obtained Raman microspectroscopic results provided a direct qualitative evidence about (a) interaction between Tris, MOPS, and HEPES buffers and cisplatin via PtN coordination covalent bond and (b) interaction of cisplatin with cysteine dominantly through PtS bond (at pH 7.4). Furthermore, this vibrational spectroscopic technique revealed a decreased dissolution of cisplatin in a particular buffering solution in the presence of NaCl abundance; kinetics of the PtN formation in the case of MOPS–NaCl medium was monitored. Moreover, spatial dissolution of cisplatin in Cys‐Tris medium was observed in situ. The particular buffering medium, containing either primary or tertiary amines, can interact with cisplatin via a coordination covalent bond. The presence of an increased NaCl concentration can partially suppress this interaction. Raman microspectroscopy, a method of vibrational spectroscopy, is a powerful technique to investigate the dissolution of cisplatin in situ. On the basis of vibrational microspectroscopic measurements, it provides direct evidence about cisplatin interactions with selected model media being widely used in biochemistry and biophysics. This interaction could influence the effectiveness of cisplatin as a drug.

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More of a misunderstanding than a real mismatch? Platinum and its affinity for aqua, hydroxido, and oxido ligands

Cited by 42 publications

References 224 publications

Advances in Toxicological Research of the Anticancer Drug Cisplatin

Advances in Toxicological Research of the Anticancer Drug Cisplatin

On the Heterogeneous Nature of Cisplatin‐1‐Methyluracil Complexes: Coexistence of Different Aggregation Modes and Partial Loss of NH₃ Ligands as Likely Explanation

Cisplatin interacting with buffering media and cysteine: Molecular insight due to Raman microspectroscopy

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More of a misunderstanding than a real mismatch? Platinum and its affinity for aqua, hydroxido, and oxido ligands

Cited by 42 publications

References 224 publications

Advances in Toxicological Research of the Anticancer Drug Cisplatin

Advances in Toxicological Research of the Anticancer Drug Cisplatin

On the Heterogeneous Nature of Cisplatin‐1‐Methyluracil Complexes: Coexistence of Different Aggregation Modes and Partial Loss of NH3 Ligands as Likely Explanation

Cisplatin interacting with buffering media and cysteine: Molecular insight due to Raman microspectroscopy

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On the Heterogeneous Nature of Cisplatin‐1‐Methyluracil Complexes: Coexistence of Different Aggregation Modes and Partial Loss of NH₃ Ligands as Likely Explanation