Platinum(IV) Prodrugs with Haloacetato Ligands in the Axial Positions can Undergo Hydrolysis under Biologically Relevant Conditions

Wexselblatt, Ezequiel; Yavin, Eylon; Gibson, Dan

doi:10.1002/anie.201300640

Cited by 87 publications

(72 citation statements)

References 30 publications

(6 reference statements)

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“…365 Detailed biophysical studies investigating the aqueous chemistry of mitaplatin and related platinum(IV) complexes with axial haloacetate ligands, found that, contrary to the typical dogma that platinum(IV) prodrugs are inert to ligand substitution, these the axial ligands of these complexes can be substituted for hydroxide under biologically relevant conditions. 366 Isotopic labelling studies revealed that the hydrolysis proceeds via the attack of a hydroxide ion on the platinum(IV) center, and not at the carbonyl of the haloacetate. Importantly, at physiological pH, however, the half-life of hydrolysis is much longer than the rate at which mitaplatin is cleared from the blood of rodents 367 and so this process likely has little influence on the in vivo effects of this compound.…”

Section: Dual-threat Platinum(iv) Prodrugs That Release Classical mentioning

confidence: 99%

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

2016

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The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive.

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Section: Dual-threat Platinum(iv) Prodrugs That Release Classical mentioning

confidence: 99%

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

2016

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“…This value is similar to that estimated from Figure S2 for the chloride substitution process. From the plot in Figure 2b, no dependence of the values of 1 k obs on the pH is evident, despite the increasing amounts of HPO 4 2− at higher pH values (pK a2 = 7.2). 50 Probably the increasing amounts of monocationic monohydroxoruthenium(II) species compensates this effect, with k′ on being determined as the k on K OS product from the general rate law indicated in eq 1, with the corresponding general mechanism.…”

Section: ■ Results and Discussionmentioning

confidence: 70%

“…Furthermore, for some of the ruthenium-(II) and ruthenium(III) complexes found to be biologically relevant, formation of the actually active ruthenium species is found to occur via initial substitution reactions; nevertheless, their speciation has not been systematically studied. 22, 23 We have recently been involved in the substitution reactivity of inert cobalt(III) complexes, with encapsulating (N) 4 macrocycles and two aqua ligands in the cis position at physiological pH, with nucleotides and nucleosides. 10,11,24 Our results have shown that speciation of these complexes in such a medium is a crucial point that has to be considered comprehensively (including the presence of hydroxo-bridged species); furthermore, tuning of the inertness can be easily achieved.…”

Section: ■ Introductionmentioning

confidence: 99%

Kinetico-mechanistic Studies on the Substitution Reactivity on the {Ru^II(bpy)₂} Core with Nucleosides and Nucleotides at Physiological pH

Vázquez

Martı́nez

2016

Inorg. Chem.

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The kinetico-mechanistic study of the substitution reactions of the aquo ligands in cis-[Ru(bpy)2(H2O)2](2+) by different nucleotides and nucleosides has been conducted at pH close to the physiological value. The concentration dependence and thermal and pressure activation parameters have been measured to ascertain the activation via which reactions take place. Substitution processes are found associatively activated for nitrogen-bonded nucleosides or nucleotides, with outer-sphere hydrogen-bonded aggregates being determinant. For reactions leading to oxygen-bonded nucleotides, the process is clearly dissociatively activated. A selectively induced lability of the inert {Ru(II)(bpy)2} core is observed on the formation of nitrogen(amide)-bonded complexes at relatively low pH values, which might be relevant for the effective intercalation of designed, ruthenium(II)-bonded, aromatic rings.

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“…Moreover, the presence of an electron-donating hydroxy ligand in the other axial position of complex 3 was expected to make conjugates derived from it more stable than analogues containing carboxylato or halo ligands about the Pt(IV) center, which are known to undergo rapid hydrolysis under biologically relevant conditions. [9] …”

Section: Resultsmentioning

confidence: 99%

Photoinduced Reduction of Pt^IVwithin an Anti-Proliferative Pt^IV-Texaphyrin Conjugate

2014

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In an effort to increase the stability and control the platinum reactivity of platinum-texaphyrin conjugates, two Pt(IV) conjugates (4 and 5, Scheme 1) were designed, synthesized, and studied for their ability to form DNA adducts. They were also tested for their anti-proliferative effects using wild-type and platinum-resistant human ovarian cancer cell lines (A2780 and 2780CP, respectively). In comparison to an analogous first generation Pt(II)-texaphyrin chimera (2, Scheme 1), conjugate 4 provided increased stability in aqueous environments. Using a combination of 1H-NMR spectroscopy and FAAS (flameless atomic-absorption spectrometry), it was found that the Pt(IV) center within conjugate 4 undergoes photo-induced reduction to Pt(II) upon exposure to glass-filtered daylight, resulting in an entity that binds DNA in a controlled manner. Under conditions where the Pt(IV) complex is reduced to the corresponding Pt(II) species, conjugates 4 and 5 demonstrated potent anti-proliferative activity in both test ovarian cancer cell lines.

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Platinum(IV) Prodrugs with Haloacetato Ligands in the Axial Positions can Undergo Hydrolysis under Biologically Relevant Conditions

Abstract: Losing ligands rapidly: Pt(IV) complexes with haloacetato ligands can hydrolyze rapidly under biological conditions (pH 7 and 37 °C, see scheme) and the rate increases with increasing pH value. Possible mechanisms for this hydrolysis are examined using H2(18)O and ESI-MS analysis.

Cited by 87 publications

References 30 publications

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Kinetico-mechanistic Studies on the Substitution Reactivity on the {Ru^II(bpy)₂} Core with Nucleosides and Nucleotides at Physiological pH

Photoinduced Reduction of Pt^IVwithin an Anti-Proliferative Pt^IV-Texaphyrin Conjugate

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Platinum(IV) Prodrugs with Haloacetato Ligands in the Axial Positions can Undergo Hydrolysis under Biologically Relevant Conditions

Abstract: Losing ligands rapidly: Pt(IV) complexes with haloacetato ligands can hydrolyze rapidly under biological conditions (pH 7 and 37 °C, see scheme) and the rate increases with increasing pH value. Possible mechanisms for this hydrolysis are examined using H2(18)O and ESI-MS analysis.

Cited by 87 publications

References 30 publications

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Kinetico-mechanistic Studies on the Substitution Reactivity on the {RuII(bpy)2} Core with Nucleosides and Nucleotides at Physiological pH

Photoinduced Reduction of PtIVwithin an Anti-Proliferative PtIV-Texaphyrin Conjugate

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Kinetico-mechanistic Studies on the Substitution Reactivity on the {Ru^II(bpy)₂} Core with Nucleosides and Nucleotides at Physiological pH

Photoinduced Reduction of Pt^IVwithin an Anti-Proliferative Pt^IV-Texaphyrin Conjugate