The influence of the ethane-1,2-diamine ligand on the activity of a monofunctional platinum complex

Graziotto, Marcus E.; Åkerfeldt, Mia C.; Gunn, Adam P; Yang, Kylie; Somerville, Mark V.; Coleman, Nicholas V.; Roberts, Blaine R.; Hambley, Trevor W.; New, Elizabeth J.

doi:10.1016/j.jinorgbio.2017.07.029

Cited by 10 publications

(3 citation statements)

References 40 publications

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“…These eight platinum complexes (Figure S4) vary in their structures, including two current anticancer therapeutics (cisplatin and oxaliplatin), their synthetic precursor (K 2 [PtCl 4 ]), two structures that have shown promise as new drug candidates (pyriplatin 51 and phenanthriplatin 38 ), another monofunctional complex ([PtCl(NH 3 ) 3 ]Cl), a transoriented complex (transplatin), and a complex with a bidentate ligand ([PtCl 2 (en)]). 52 By covering a wide range of structures, we hoped to demonstrate that the array could discriminate and identify multiple coordination spheres in a single assay. Similar to the metal screen, the normalized fluorescence response of the six sensors with each platinum complex produced a distinct pattern (Figure S5), so we sought to further classify these results using multivariate analysis.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Therefore, as well as testing platinum complexes that are clinically approved for cancer treatment, we selected a number of other platinum complexes to test in the array. These eight platinum complexes (Figure S4) vary in their structures, including two current anticancer therapeutics (cisplatin and oxaliplatin), their synthetic precursor (K 2 [PtCl 4 ]), two structures that have shown promise as new drug candidates (pyriplatin and phenanthriplatin), another monofunctional complex ([PtCl(NH 3 ) 3 ]Cl), a trans -oriented complex (transplatin), and a complex with a bidentate ligand ([PtCl 2 (en)]) . By covering a wide range of structures, we hoped to demonstrate that the array could discriminate and identify multiple coordination spheres in a single assay.…”

Section: Resultsmentioning

confidence: 99%

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A Versatile Fluorescent Sensor Array for Platinum Anticancer Drug Detection in Biological Fluids

et al. 2021

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Platinum complexes remain frontline anticancer therapies, even after 50 years of usage in clinical applications. However, there is still a lack of methodology to robustly detect and quantify these complexes in biological fluids. We report here a fluorescent sensor array comprising six sensors that demonstrates progress toward the detection of platinum levels in chemotherapy patients. Linear discriminant analysis was performed to examine each multidimensional data set, and the array was able to discriminate platinum from other biologically relevant metals and heavy metals and separately able to differentiate and identify platinum complexes with different coordination environments with 100% accuracy. Finally, the array showed sensitivity to various cisplatin and oxaliplatin concentrations in human plasma and was able to discriminate between a cohort of 27 cancer patients at different stages of platinum treatment. We envisage that our array system could lead to a better understanding of blood platinum concentrations of chemotherapy patients and could inform the modification of dosage regimes to minimize dose-limiting side effects.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Versatile Fluorescent Sensor Array for Platinum Anticancer Drug Detection in Biological Fluids

et al. 2021

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“…The latter,i nstead, suggests that the mechanism of binding of phenanthriplatin to DNA involves the rapid intercalation of the phenanthridiner ing that localizes the platinum center on DNA where it irreversibly binds to DNA bases forming covalent bonds. All this information, even contradictory,c oming from previousi nvestigationso ft he specific cytotoxicity of phenanthriplatin compared to that of other Pt II drugsh as inspired us to study the activation and interaction mechanismso faset of am ono-functional platinum drugs in an attempt to find ar elationship between structuresa nd anticancer activity.P henanthriplatin (Phen), pyriplatin (Pyr) ande npyriplatin (Enpyr) [9,19] mono-functional platinum drugs have been selected as they show very different cytotoxic effects. Enpyriplatin, ([PtCl(en)-(py)] + ,a sr eported in Scheme 1, is as tructurala nalogous of pyriplatin characterizedb yt he presence of an ethane-1,2-diamine (en) ligand,r eplacing the two cis-ammine ligands of pyriplatin.…”

Section: Introductionmentioning

confidence: 99%

Rationalization of the Superior Anticancer Activity of Phenanthriplatin: An In‐Depth Computational Exploration

Dabbish

Russo

Sicilia

2019

Chemistry A European J

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In the effort to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents, a large number of cisplatin variants continues today to be prepared and tested. One of the applied strategies is to use monofunctional platinum complexes that, unlike traditional bifunctional compounds, are able to form only a single covalent bond with nuclear DNA. Chirality, aquation reaction, interaction with guanine and N‐acetyl methionine as well as, intercalation into, binding to and distortion of DNA have been investigated by using both quantum mechanical DFT and molecular dynamics computations aiming at contributing to the elucidation of the molecular mechanism underlying the significantly enhanced spectrum of activity of the monofunctional PtII drug phenanthriplatin. Analogous calculations have been performed in parallel for other two less potent monofunctional PtII drugs, pyriplatin and enpyriplatin, which show very different cytotoxic effects.

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An Antitumor Bis(N‐Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target

Yang

Lok

et al. 2019

Angewandte Chemie

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New anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe arare example of an antitumor Pt II complex targeting at umor-associated protein, rather than DNA, under cellular conditions.Complex [(bis-NHC)Pt(bt)]PF 6 (1a;H bt = 1-(3-hydroxybenzo-[b]thiophen-2-yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry.Anunbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as am olecular target of 1a.A ccordingly, 1a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. Ab is-NHC-ligated Pt species generated from the hydrolysis of 1a forms adducts with thiols and appears to target an active-site cysteine of ASNS.

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The influence of the ethane-1,2-diamine ligand on the activity of a monofunctional platinum complex

Cited by 10 publications

References 40 publications

A Versatile Fluorescent Sensor Array for Platinum Anticancer Drug Detection in Biological Fluids

A Versatile Fluorescent Sensor Array for Platinum Anticancer Drug Detection in Biological Fluids

Rationalization of the Superior Anticancer Activity of Phenanthriplatin: An In‐Depth Computational Exploration

An Antitumor Bis(N‐Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target

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