Conformational isomerism of trans-[Pt(NH2C6H11)2I2] and the classical Wernerian chemistry of [Pt(NH2C6H11)4]X2 (X=Cl, Br, I)

Johnstone, Timothy C.; Lippard, Stephen J.

doi:10.1016/j.poly.2012.08.010

Cited by 8 publications

(4 citation statements)

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“…An MM geometry optimization was carried out for each conformer using Gaussian03 . The universal force field was employed using technical details described previously …”

Section: Methodsmentioning

confidence: 99%

The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding

Johnstone

Lippard

2014

J. Am. Chem. Soc.

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The monofunctional platinum complex cis-[Pt(NH3)2Cl(Am)]+, also known as phenanthriplatin, where Am is the N-heterocyclic base phenanthridine, has promising anticancer activity. Unlike bifunctional compounds such as cisplatin, phenanthriplatin can form only one covalent bond to DNA. Another distinguishing feature is that phenanthriplatin is chiral. Rotation about the Pt–N bond of the phenanthridine ligand racemizes the complex, and the question arises as to whether this process is sufficiently slow under physiological conditions to impact its DNA-binding properties. Here we present the results of NMR spectroscopic, X-ray crystallographic, molecular dynamics, and density functional theoretical investigations of diastereomeric phenanthriplatin analogs in order to probe the internal dynamics of phenanthriplatin. These results reveal that phenanthriplatin rapidly racemizes under physiological conditions. The information also facilitated the interpretation of the NMR spectra of small molecule models of phenanthriplatin-platinated DNA. These studies indicate, inter alia, that one diastereomeric form of the complexes cis-[Pt(NH3)2(Am)(R-Gua)]2+, where R-Gua is 9-methyl- or 9-ethylguaine, is preferred over the other, the origin of which stems from an intramolecular interaction between the carbonyl oxygen of the platinated guanine base and a cis-coordinated ammine. The relevance of this finding to the DNA-damaging properties of phenanthriplatin and its biological activity is discussed.

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“…An MM geometry optimization was carried out for each conformer using Gaussian03 . The universal force field was employed using technical details described previously …”

Section: Methodsmentioning

confidence: 99%

The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding

Johnstone

Lippard

2014

J. Am. Chem. Soc.

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“…DNA polymerase η, a translesion synthase capable of bypassing 1,2-intrastand cross-links formed by cisplatin, is able to insert the correct nucleotide opposite the phenanthriplatin-bound guanine, but cannot proceed further . A detailed mechanism of DNA polymerase η inhibition was inferred from X-ray crystallographic data, which suggested that, despite the rotational freedom typically observed about Pt–amine bonds, the phenanthridine ring imposes a thermodynamic diastereoselectivity on the adduct that plays a significant role in blocking polymerase progression. , Studies with Escherichia coli resembling those conducted by Rosenberg further revealed that phenanthriplatin induces filamentous cell growth in a manner similar to that of cisplatin . Monofunctional platinum(II) complexes with little biological activity in cultured mammalian cancer cells were not able to replicate this result.…”

Section: Platinum(ii) Compounds With a Mechanism Of Action Different ...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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“…Trans complexes can also be prepared directly from [PtL 4 ]X 2 compounds without the use of hydrochloric acid. Upon heating [PtL 4 ]X 2 as a suspension in an organic solvent or as a solid under vacuum, the outer-sphere halides substitute the inner-sphere amine or N -heterocycle, exclusively generating the trans isomer. − In an attempt to make trans -[PtL 2 Cl 2 ], where L is imidazole, [PtL 4 ]Cl 2 was treated with HCl. Instead of obtaining the expected product, trans -[PtL 2 Cl 2 ], only platinum(IV) complexes were obtained .…”

Section: Synthesis Of Platinum(ii) Complexesmentioning

confidence: 99%