Monofunctional and Higher-Valent Platinum Anticancer Agents

Johnstone, Timothy C.; Wilson, Justin J.; Lippard, Stephen J.

doi:10.1021/ic400538c

Cited by 201 publications

(157 citation statements)

References 199 publications

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“…The complex that gave the best results, far better than those of oxaliplatin, was cationic cis-diamminepyridinechloroplatinum(II), also referred to as cDPCP or pyriplatin (figure 1) [27]. The anti-cancer activity of this compound had been investigated previously in an animal model [28], but only a small number of follow-up studies on related compounds were performed [29]. In addition to significant organic character and cationic charge, pyriplatin is of interest because only one labile chloride ligand is present in the coordination sphere.…”

Section: Monofunctional Platinum Anti-cancer Agents (A) Pyriplatin: Rmentioning

confidence: 99%

Third row transition metals for the treatment of cancer

Johnstone

Suntharalingam

Lippard

2015

Phil. Trans. R. Soc. A.

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Platinum compounds are a mainstay of cancer chemotherapy, with over 50% of patients receiving platinum. But there is a great need for improvement. Major features of the cisplatin mechanism of action involve cancer cell entry, formation mainly of intrastrand cross-links that bend and unwind nuclear DNA, transcription inhibition and induction of cell-death programmes while evading repair. Recently, we discovered that platinum cross-link formation is not essential for activity. Monofunctional Pt compounds such as phenanthriplatin, which make only a single bond to DNA nucleobases, can be far more active and effective against a range of tumour types. Without a cross-link-induced bend, monofunctional complexes can be accommodated in the major groove of DNA. Their biological mechanism of action is similar to that of cisplatin. These discoveries opened the door to a large family of heavy metal-based drug candidates, including those of Os and Re, as will be described.

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Section: Monofunctional Platinum Anti-cancer Agents (A) Pyriplatin: Rmentioning

confidence: 99%

Third row transition metals for the treatment of cancer

Johnstone

Suntharalingam

Lippard

2015

Phil. Trans. R. Soc. A.

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“…Monofunctional platinum compounds differ from the clinically used bifunctional species in that they form only one covalent bond to DNA (17). Phenanthriplatin, or cis-diamminephenanthridinechloroplatinum(II), is a monofunctional platinum agent that has displayed very promising anticancer activity (Fig.…”

Section: Significancementioning

confidence: 99%

Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage

Gregory

Park

Johnstone

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases ν, ζ, and κ and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol η, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol η complexed with site-specifically platinated DNA at both the insertion and +1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol η in a manner distinct from that of cisplatin-DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol η expression, phenanthriplatin is highly toxic to both Pol η+ and Pol η− cells. Given that increased expression of Pol η is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin.cancer therapy | monofunctional platinum drug candidates | pol eta | X-ray crystallography

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“…For example, encapsulating platinum-based anti-cancer drugs can diminish their accumulation in the kidneys, increase their blood circulation time, and increase overall efficacy. 40,41 Circulation time and organ accumulation of magnetite nanoparticles is similarly affected by encapsulation. 42 Results like these underline the importance of finding new ways of delivering drugs.…”

Section: Limitationsmentioning

confidence: 99%

Featured Article: Nanoenhanced matrix metalloproteinase-responsive delivery vehicles for disease resolution and imaging

McCarthy

Nazem

McNeilan

et al. 2016

Exp Biol Med (Maywood)

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The wide array of proteases, including matrix metalloproteinases, produced in response to many pathogenic insults, confers a unique proteolytic signature which is often disease specific and provides a potential therapeutic target for drug delivery. Here we propose the use of collagen-based nanoenhanced matrix metalloproteinase-responsive delivery vehicles that display matrix metalloproteinase-specific degradation in diverse in vitro models of proteolysis. We demonstrate that collagen particles comprised of protease substrates (primarily collagen) can be made of uniform size and loaded efficiently with assorted cargo including fluorescently labeled mesoporous silica, magnetic nanoparticles, proteins and antioxidants. We also demonstrate that pathologic concentrations of proteases produced in situ or in vitro display protease-specific cargo release. Additionally, we show that the collagen-based particles display bright fluorescence when loaded with a fluorophore, and have the potential to be used as vehicles for targeted delivery of drugs or imaging agents to regions of high proteolytic activity.

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Monofunctional and Higher-Valent Platinum Anticancer Agents

Cited by 201 publications

References 199 publications

Third row transition metals for the treatment of cancer

Third row transition metals for the treatment of cancer

Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage

Featured Article: Nanoenhanced matrix metalloproteinase-responsive delivery vehicles for disease resolution and imaging

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