Platinum(IV) Complex with Adamantylamine as Nonleaving Amine Group:  Synthesis, Characterization, and in Vitro Antitumor Activity against a Panel of Cisplatin-Resistant Cancer Cell Lines

F, Zak; Tuřánek, Jaroslav; Kroutil, Aleš; Sova, Petr; Mistr, A.; Poulová, Anna; Mikolin, Petr; Žák, Zdirad; Kašná, Andrea; Záluská, Dana; Neča, Jiřı́; Šindlerová, Lenka; Kozubı́k, Alois

doi:10.1021/jm030858+

Cited by 71 publications

(21 citation statements)

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“…LA-12, [( OC -6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum (IV)], is a hydrophobic platinum(IV) complex structurally similar to JM216, which contains 1-adamantylamine instead of cyclohexylamine non-leaving ligand [6] which provides this drug different properties. LA-12 has shown a higher cytotoxicity than JM216 when tested on a panel of 14 cancer cell lines of various origin and different cisplatin sensitivity [6,7] and no cross-resistance with cisplatin [6,8].…”

Section: Introductionmentioning

confidence: 99%

“…LA-12 has shown a higher cytotoxicity than JM216 when tested on a panel of 14 cancer cell lines of various origin and different cisplatin sensitivity [6,7] and no cross-resistance with cisplatin [6,8]. LA-12 has also displayed (i) higher antitumor activity in comparison with cisplatin and JM216, (ii) favourable pharmacokinetics and (iii) relatively low acute toxicity in a panel of pre-clinical in vivo studies [9-11].…”

Section: Introductionmentioning

confidence: 99%

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The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin

et al. 2010

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BackgroundCisplatin and its derivatives are commonly used anti-cancer drugs. However, cisplatin has clinical limitations including serious side effects and frequent emergence of intrinsic or acquired resistance. Thus, the novel platinum(IV) complex LA-12 represents a promising treatment modality, which shows increased intracellular penetration resulting in improved cytotoxicity in various cancer cell lines, including cisplatin resistant cells.ResultsLA-12 disrupts cellular proliferation regardless of the p53 status in the cells, however the potency of the drug is greatly enhanced by the presence of a functional p53, indicating several mechanisms of action. Similarly to cisplatin, an interaction of LA-12 with molecular chaperone Hsp90 was proposed. Binding of LA-12 to Hsp90 was demonstrated by Hsp90 immunoprecipitation followed by platinum measurement using atomic absorption spectrometry (AAS). An inhibitory effect of LA-12 on Hsp90 chaperoning function was shown by decrease of Hsp90-assisted wild-type p53 binding to p21WAF1 promoter sequence in vitro and by accelerated ubiqutination and degradation of primarily unfolded mutant p53 proteins in cells exposed to LA-12.ConclusionsTo generalize our findings, LA-12 induced degradation of other Hsp90 client proteins such as Cyclin D1 and estrogen receptor was shown and proved as more efficient in comparison with cisplatin. This newly characterised molecular mechanism of action opens opportunities to design new cancer treatment strategy profitable from unique LA-12 properties, which combine DNA damaging and Hsp90 inhibitory effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin

et al. 2010

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“…LA-9 represents a four-coordinate(II), and LA-12 an octahedral six-coordinate platinum complex containing a bulky nonleaving hydrophobic (lipophilic) ligand—adamantylamine [15]. Since the early studies by Rosenberg et al [16] it has been known that platinum(IV) as well as platinum(II) complexes can display antitumor properties.…”

Section: Development Of Platinum(iv) Complexes With Adamantylaminementioning

confidence: 99%

Novel Anticancer Platinum(IV) Complexes with Adamantylamine: Their Efficiency and Innovative Chemotherapy Strategies Modifying Lipid Metabolism

et al. 2008

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The impressive impact of cisplatin on cancer on one side and severe side effects, as well as the development of drug resistance during treatment on the other side, were the factors motivating scientists to design and synthesize new more potent analogues lacking disadvantages of cisplatin. Platinum(IV) complexes represent one of the perspective groups of platinum-based drugs. In this review, we summarize recent findings on both in vitro and in vivo effects of platinum(IV) complexes with adamantylamine. Based on a literary overview of the mechanisms of activity of platinum-based cytostatics, we discuss opportunities for modulating the effects of novel platinum complexes through interactions with apoptotic signaling pathways and with cellular lipids, including modulations of the mitochondrial cell death pathway, oxidative stress, signaling of death ligands, lipid metabolism/signaling, or intercellular communication. These approaches might significantly enhance the efficacy of both novel and established platinum-based cytostatics.

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“…This motif has been employed in a number of other compounds including a close relative of satraplatin, c , c , t -ammineadamantylamine-dichlorodiacetatoplatinum(IV), also known as LA-12 [9]. Mixed amine/ammine structures also occur in cycloplatam and picoplatin, Pt(II) compounds that have been entered into Phase II and III clinical trials, respectively [10-12].…”

Section: Introductionmentioning

confidence: 99%

Improvements in the synthesis and understanding of the iodo-bridged intermediate en route to the Pt(IV) prodrug satraplatin

Johnstone

Lippard

2015

Inorganica Chimica Acta

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Mixed amine/ammine motifs are important features in newer generation platinum anticancer agents, including the Pt(IV) prodrug satraplatin. One synthetic route that can be used to access platinum molecules with such structures exploits the trans effect during NH3-mediated cleavage of iodo-bridged platinum(II) dimers of the form [Pt(Am)I(μ-I)]2, where Am is an amine. A clear picture of the nature of these dimers that is consistent with the reactivity they exhibit has remained elusive. Moreover, technical aspects of this chemistry have impeded its more widespread use. We present here an improved strategy that permits isolation and use of [Pt(Am)I(μ-I)]2, where Am is cyclohexylamine, within minutes as opposed to weeks, as previously reported. A detailed spectroscopic, crystallographic, and chromatographic investigation of this intermediate in the synthesis of satraplatin is also presented with a discussion of the ability of both cis and trans isomers of the dimer to produce exclusively cis-[Pt(NH2C6H11)(NH3)I2] upon treatment with NH3.

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Platinum(IV) Complex with Adamantylamine as Nonleaving Amine Group: Synthesis, Characterization, and in Vitro Antitumor Activity against a Panel of Cisplatin-Resistant Cancer Cell Lines

Cited by 71 publications

References 6 publications

The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin

The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin

Novel Anticancer Platinum(IV) Complexes with Adamantylamine: Their Efficiency and Innovative Chemotherapy Strategies Modifying Lipid Metabolism

Improvements in the synthesis and understanding of the iodo-bridged intermediate en route to the Pt(IV) prodrug satraplatin

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