Oxa-aza Crown Ethers as Ligands for Mixed-Ligand Cisplatin Derivatives and Dinuclear Platinum Anticancer Drugs

Jansen, Bart M. P.; Wielaard, Peter; Dulk, Hans den; Brouwer, Jaap; Reedijk, J.

doi:10.1002/1099-0682(200209)2002:9<2375::aid-ejic2375>3.0.co;2-b

Cited by 13 publications

(9 citation statements)

References 28 publications

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“…Jansen and co‐workers prepared cisplatin derivatives in which the platinum center is coordinated directly to the nitrogen atom in an aza crown ether. Although these compounds have higher DNA binding capacity, their biological activity is either negligible or lower than that of cisplatin 86…”

Section: Biological Activity Of Crown Ethersmentioning

confidence: 99%

Biomedical Potentials of Crown Ethers: Prospective Antitumor Agents

2008

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Crown ethers are of enormous interest and importance in chemistry, biochemistry, materials science, catalysis, separation, transport and encapsulated processes, as well as in the design and synthesis of various synthetic systems with specific properties, diverse capabilities, and programmable functions. Classical crown ethers are macrocyclic polyethers that contain 3-20 oxygen atoms separated from each other by two or more carbon atoms. They are exceptionally versatile in selectively binding a range of metal ions and a variety of organic neutral and ionic species. Crown ethers are currently being studied and used in a variety of applications beyond their traditional place in chemistry. This review presents additional applications and the ever-increasing biomedical potentials of these intriguing compounds, with particular emphasis on the prospects of their relevance as anticancer agents. We believe that further research in this direction should be encouraged, as crown compounds could either induce toxicities that are different from those of conventional antitumor drugs, or complement drugs in current use, thereby providing a valuable adjunct to therapy.

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Section: Biological Activity Of Crown Ethersmentioning

confidence: 99%

Biomedical Potentials of Crown Ethers: Prospective Antitumor Agents

2008

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“…Growth inhibition by the complex cis-(Cl,Cl)-[RuCl 2 (NO)(terpy)]Cl (1) was determined using an MTT-based assay 33 using a previously described method. 34 In the cytotoxicity test, a DMSO stock solution was used due to the poor solubility of the complex in water (∼3 × 10 −3 M at 310 K) in order to have a better comparison with other cytotoxic compounds (see Section 3.3 below). The cells had been exposed to the compound for a relatively long time (3 days), to allow the compound to be able to reach DNA, or another biological target, and act on this level.…”

Section: Cell Lines and Cytotoxicity Testmentioning

confidence: 99%

Synthesis, characterization, in vitro antitumor activity, DNA-binding properties and electronic structure (DFT) of the new complex cis-(Cl,Cl)[RuIICl2(NO+)(terpy)]Cl

et al. 2005

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The complex cis-(Cl,Cl)-[RuCl2(terpy)(NO)]Cl (1) has been synthesized by the reaction of [RuCl3(H2O)2(NO)] with terpyridine (terpy) and characterized by various spectroscopic, analytical techniques and using electronic structure calculation (DFT) methods. The cytotoxic activity and the DNA-binding properties of have also been studied using biochemical techniques. The results establish unequivocally that corresponds to a so-called [RuNO]6 species, which readily releases the nitrosyl ligand upon irradiation with a mercury lamp in acetonitrile solution. DFT calculations provided a satisfactory description of structural, bonding, electronic and related properties of the new compound and throw light on the mechanism of the photo-induced NO release. Screening on A2780 (human ovarian carcinoma) cell lines showed significant cytotoxicity with an IC50 value of 0.49 microM. 31P and 23Na NMR spectroscopy along with electrophoretic mobility studies illustrated that complex primarily binds by coordination to DNA without any pi-interaction between the planar terpy ligand and the DNA bases, while weak electrostatic interactions could not be excluded. Studies on the inhibition of the restriction enzymes DraI and SmaI revealed that prefers the guanine and cytosine bases of DNA.

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“…It is well-known that the uptake of cisplatin is influenced by factors such as sodium and potassium ion concentration, and the participation of transporter molecules or gated channels has been postulated in addition to passive diffusion. In 2002, Jansen et al 27 described the possibility of incorporating a diaza crown ether as linker in binuclear platinum complexes. They assessed the antitumor response of compounds DAO18 and DAO15 (see Scheme 2) against cell lines A2780 and 2780cis but did not find cytotoxicity, so that the idea of using aza crowns as linkers for the design of binuclear antineoplastic metal-drugs was abandoned.…”

Section: ■ Discussionmentioning

confidence: 99%

“…In addition to reports on functionalized crown ethers capable of binding and cleaving DNA, research within this field has been also focused on compounds that inhibit tumor-cell growth by disrupting potassium ion homeostasis, which, in turn, leads to cell cycle perturbations and apoptosis . The cytotoxicity of platinum complexes containing crown ether and aza crown ether platforms has been also examined, although such studies are quite scarce. − …”

Section: Introductionmentioning

confidence: 99%

Further Approaches in the Design of Antitumor Agents with Response to Cell Resistance: Looking toward Aza Crown Ether-dtc Complexes

et al. 2020

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The dianionic aza crown ether-dtc N,N′-bis-(dithiocarbamate)-1,10-diaza-18-crown-6 (L 2− ) is a versatile ligand capable of yielding binuclear complexes with group 10 elements, also known as Ni-triade, [μ-(κ 2 -S,-S′-L)M 2 (PPh 3 ) 4 ]Cl 2 (M = Pd (1), Pt (2)), [μ-(κ 2 -S,-S′-L)M 2 (PPh 3 ) 4 ](BPh 4 ) 2 (M = Pd (3), Pt (4)), and μ-(κ-S,-S′-L)Ni 2 (PPh 3 ) 2 Cl 2 ( 5), and has proven to be an excellent option to the design of metal-based drugs able to provide multiple response to cell resistance. Palladium and platinum complexes, 1 and 2, were tested for cytotoxicity in the human cervix carcinoma cell line HeLa-229, the human ovarian carcinoma cell line A2780, and the cisplatin-resistant mutant A2780cis, finding significant activity toward all three cancer cell lines, with low micromolar IC 50 values, comparable to cisplatin. Markedly, against the cisplatin resistant cell line A2780cis, compound 2 exhibits better cytotoxic activity than the clinical drug (IC 50 = 2.3 ± 0.2 μM for 2 versus 3.6 ± 0.5 μM for cisplatin). Moreover, an enhancement of the antitumor response is achieved when adding an equimolar amount of alkali metal chloride (NaCl or KCl) to the medium, for instance, testing compound 1 against the cisplatin-resistant A2780cis cells, the IC 50 decreases from 9.3 ± 0.4 to 7.4 ± 0.3 and 5.4 ± 0.1 μM, respectively, after addition of the salt solution. For the platinum derivative 2, the IC 50 improves by ca. 40% reaching 1.3 ± 0.1 μM when potassium chloride is added. Likewise, the resistant factor found for 2 (RF = 1) confirms that this complex circumvents cisplatin-resistance in A2780cis and is improved with the addition of potassium chloride (RF = 0.65). The presence of the aza crown ether moiety as linker in the systems studied herein is a key point since, in addition to allowing and facilitating interaction with alkali metal ions, this unit is flexible enough to adapt to a variety of environments, as confirmed by the Xray crystal structures described, where different conformations and ways to fold in are found. In order to gain insight into the electronic and structural facts involved in the interaction of complex 2 with the alkali metal ions, a DFT study was performed, and the description of the molecular electrostatic potentials (MEPs) is also presented.

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Oxa-aza Crown Ethers as Ligands for Mixed-Ligand Cisplatin Derivatives and Dinuclear Platinum Anticancer Drugs

Cited by 13 publications

References 28 publications

Biomedical Potentials of Crown Ethers: Prospective Antitumor Agents

Biomedical Potentials of Crown Ethers: Prospective Antitumor Agents

Synthesis, characterization, in vitro antitumor activity, DNA-binding properties and electronic structure (DFT) of the new complex cis-(Cl,Cl)[RuIICl2(NO+)(terpy)]Cl

Further Approaches in the Design of Antitumor Agents with Response to Cell Resistance: Looking toward Aza Crown Ether-dtc Complexes

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