Combinatorial discovery of new asymmetric platinum anticancer complexes is made possible with solid-phase synthetic methods

Zutphen, Steven van; Stone, Elizabeth A; Rijt, Sabine van; Robillard, Marc S.; Marel, Gijs A. van der; Overkleeft, Herman S.; Dulk, Hans den; Brouwer, Jaap; Reedijk, Jan

doi:10.1016/j.jinorgbio.2005.06.033

Cited by 12 publications

(3 citation statements)

References 23 publications

(31 reference statements)

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“…The peptide was able to enhance platination of poly(dA) tracts over poly(dG) tracts, the latter of which are preferentially platinated by cisplatin. The ability to explore a much wider range of platinum(II)–peptide conjugates arose when synthetic strategies compatible with solid-phase peptide synthesis were developed. − This chemistry involved linking the platinum complex to the peptide through a functionalized ethylenediamine nonleaving group ligand. The platinum chemistry could be performed on the solid support, and the complex survived harsh deprotection and cleavage conditions.…”

Section: Platinum(ii) Compounds With a Mechanism Of Action Similar To...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: Platinum(ii) Compounds With a Mechanism Of Action Similar To...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 application of combinatorial synthetic strategies , would substantially reduce time and effort in developing a library of these complexes for biological use. Combinatorial syntheses typically require one-pot reactions that combine different building blocks to access a set of diverse molecular entities. − In the context of medicinal inorganic chemistry, combinatorial approaches have been applied to generate libraries of anticancer ruthenium and platinum complexes. − Importantly, these studies identified promising anticancer drug candidates, validating the use of combinatorial chemistry for the discovery of new inorganic therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Combinatorial Synthesis to Identify a Potent, Necrosis-Inducing Rhenium Anticancer Agent

et al. 2019

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Combinatorial synthesis can be applied for developing a library of compounds that can be rapidly screened for biological activity. Here, we report the application of microwave-assisted combinatorial chemistry for the synthesis of 80 rhenium(I) tricarbonyl complexes bearing diimine ligands. This library was evaluated for anticancer activity in three different cancer cell lines, enabling the identification of three lead compounds with cancer cell growth-inhibitory activities of less than 10 μM. These three lead structures, Re-9B, Re-9C, and Re-9D, were synthesized independently and fully characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography. The most potent of these three complexes, Re-9D, was further explored to understand its mechanism of action. Complex Re-9D is equally effective in both wild-type and cisplatin-resistant A2780 ovarian cancer cells, indicating that it circumvents cisplatin resistance. This compound was also shown to possess promising activity against ovarian cancer tumor spheroids. Additionally, flow cytometry showed that Re-9D does not induce cell cycle arrest or flipping of phosphatidylserine to the outer cell membrane. Analysis of the morphological changes of cancer cells treated with Re-9D revealed that this compound gives rise to rapid plasma membrane rupture. Collectively, these data suggest that Re-9D induces necrosis in cancer cells. To assess the in vivo biodistribution and stability of this compound, a radioactive 99mTc analogue of Re-9D, 99mTc-9D(H2O), was synthesized and administered to naı̈ve BALB/c mice. Results of these studies indicate that 99mTc-9D(H2O) exhibits high metabolic stability and a distinct biodistribution profile. This research demonstrates that combinatorial synthesis is an effective approach for the development of new rhenium anticancer agents with advantageous biological properties.

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“…232 In recent years, this approach has also been utilised for high-throughput anti-cancer ruthenium and platinum complex synthesis and cytotoxicity screening by Ang, Lippard, Meggers, Reedijk, and Ziegler et al . 233–237 Similarly, the Wilson group applied a one-pot reaction containing three components, namely, an aniline, a pyridine ligand tethered to an aldehyde, and rhenium( i ) pentacarbonyl chloride, for the rapid synthesis of a series of rhenium( i ) tricarbonyl complexes with different structural motifs. 238 Through such a combinatorial synthesis methodology, complex 4-23 (Fig.…”

Section: Anti-tumor Organometallics Triggering Cell Death Pathwaysmentioning

confidence: 99%

Organometallic anti-tumor agents: targeting from biomolecules to dynamic bioprocesses

2023

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Combinatorial discovery of new asymmetric platinum anticancer complexes is made possible with solid-phase synthetic methods

Cited by 12 publications

References 23 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

Combinatorial Synthesis to Identify a Potent, Necrosis-Inducing Rhenium Anticancer Agent

Organometallic anti-tumor agents: targeting from biomolecules to dynamic bioprocesses

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