11 research outputs found
Cytotoxicity, mutagenicity, cellular uptake, DNA and glutathione interactions of lipophilic trans-platinum complexes tethered to 1-adamantylamine
No full textSynthesis, Biophysical Studies, and Antiproliferative Activity of Platinum(II) Complexes Having 1,2-Bis(aminomethyl)carbobicyclic Ligands
No full textA selected chemical library of six platinum(II) complexes having 1,2-bis(aminomethyl)carbobicyclic ligands were synthesized after a rational design in order to evaluate their antiproliferative activity and the structure–activity relationships. The cytotoxicity studies were performed using cancer cell lines sensitive (A2780) and resistant (A2780R) to cisplatin. Excellent cytotoxicity was observed for most of complexes, which presented better resistance factors than cisplatin against the A2780R cell line. The interaction of these complexes with DNA, as the target biomolecule, was evaluated by several methods: DNA−platinum binding kinetics, changes in the DNA melting temperature, evaluation of the unwinding angle of supercoiled DNA, evaluation of the interstrand cross-links, and replication mapping. The kinetics of the interaction with glutathione was also investigated to better understand the resistant factors observed for the new complexes
Insights into DNA platination within unusual structural settings
No full text2D [1H, 15N] HSQC NMR spectroscopy has been used to monitor reaction and product formation between [Pt(15NH3)2I2] and nucleic acids possessing irregular topologies and containing site specific phosphorothioate substitution in the phosphodiester backbone. Comparison of the reaction profiles of dimer nucleic acids with and without phosphorothioate substitution is made with their short nucleic acid counterparts containing the key dimer components. Whereas d(GpA) is relatively unreactive towards [Pt(15NH3)2I2], NMR evidence suggests that the tandem sheared mismatch duplex d(GCG3pAGC)2 reacts to form the head-to-tail inter-strand G3-N7-Pt-G3-N7 cross-link. The equivalent phosphorothioate R,S-d(GsA) reacts to form a mono-iodo, mono-sulphur adduct, whereas the tandem sheared mismatch phosphorothioate duplex d(GCGsAG5C)2 (VIs) reacts to form the unusual intra-strand macrochelate [Pt(15NH3)2{d(VIs-G5-N7)},S]2+ in which platinum is attached at both sulphur and G5-N7. Experimental evidence supports the formation of a stabilized mismatch duplex in which platinum is attached to two nitrogen centres in the sequence d(CGCGpTGCG) in contrast to R,S-d(CGCGsT5GCG) for which NMR evidence supports macrochelate-stabilized hairpin loop formation cross-linked at both phosphorothioate sulphur and T5-N
Photoactivation of trans diamine platinum complexes in aqueous solution and effect on reactivity towards nucleotides
No full textWe show that UVA irradiation (365 nm) of the Pt-IV complex trans,trans,trans-[(PtCl2)-Cl-IV(OH)(2)(dimethylamine) (isopropylamine)] (1), induces reduction to Pt-II photoproducts. For the mixed amine Pt-II complex, trans[(PtCl2)-Cl-II(isopropylamine)(methylamine)] (2), irradiation at 365 nm increases the rate and extent of hydrolysis, triggering the formation of diaqua species. Additionally, irradiation increases the extent of reaction of complex 2 with guanosine-5'-monophosphate and affords mainly the bis-adduct, while reactions with adenosine-5'-monophosphate and cytidine-5'-monophosphate give rise only to mono-nucleotide adducts. Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes 1 and 2, and their photophysical and photochemical properties. UVA-irradiation can contribute to enhanced cytotoxic effects of diamine platinum drugs with trans geometry
Interactions of DNA with a new Platinum(IV) Azide Dipyridine complex activated by UVA and visible light : relationship to toxicity in tumor cells
No full textThe Pt IV diazido complex trans,trans,trans-[Pt(N 3) 2(OH) 2(pyridine) 2] (1) is unreactive in the dark but is cytotoxic when photoactivated by UVA and visible light. We have shown that 1 when photoactivated accumulates in tumor cells and binds strongly to nuclear DNA under conditions in which it is toxic to tumor cells. The nature of the DNA adducts, including conformational alterations, induced by photoactivated 1 are distinctly different from those produced in DNA by conventional cisplatin or transplatin. In addition, the observation that major DNA adducts of photoactivated 1 are able to efficiently stall RNA polymerase II more efficiently than cisplatin suggests that transcription inhibition may contribute to the cytotoxicity levels observed for photoactivated 1. Hence, DNA adducts of 1 could trigger a number of downstream cellular effects different from those triggered in cancer cells by DNA adducts of cisplatin. This might lead to the therapeutic effects that could radically improve chemotherapy by platinum complexes. The findings of the present work help to explain the different cytotoxic effects of photoactivated 1 and conventional cisplatin and thereby provide new insights into mechanisms associated with the antitumor effects of platinum complexes photoactivated by UVA and visible light. © 2012 American Chemical Society
Transplatin is cytotoxic when photoactivated:enhanced formation of DNA cross-links
No full textIt is well-known that although cisplatin, [cis-[PtCl2(NH3)(2)], is an anticancer drug, its isomer transplatin is not cytotoxic. Here we show that transplatin is almost as cytotoxic as cisplatin when treated cells (human keratinocytes HaCaT and ovarian cancer A2780 cells) are irradiated with UVA light (50 min, 1.77 mW cm(-2)). Chemical studies show that light activates both chloride ligands of transplatin, and experiments on pSP73 plasmid DNA and a 23 base-pair DNA duplex show that irradiation can greatly enhance formation of interstrand cross-links and of DNA-protein cross-links (which are not formed in the dark). Comet assays showed that UVA irradiation of transplatin-treated cells resulted in an increased inhibition of H2O2-induced DNA migration, supporting the conclusion that the cytotoxicity of photoactivated transplatin is mainly due to formation of DNA interstrand and DNA-protein cross-links.</p
A potent cytotoxic photoactivated platinum complex
No full textWe show by x-ray crystallography that the complex trans, trans, trans-[Pt(N-3)(2)(OH)(2)(NH3)(py)] (1) contains an octahedral Pt-IV center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13-80 x more cytotoxic than the Pt-II anticancer drug cisplatin, and ca. 15 x more cytotoxic toward cisplatin-resistant human ovarian cancer cells. Cisplatin targets DNA, and DNA platination levels induced in HaCaT skin cells by 1 were similar to those of cisplatin. However, cisplatin forms mainly intrastrand cis diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex 1 rapidly forms unusual trans azido/guanine, and then trans diguanine Pt-II adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA-protein cross-links were also detected. Importantly, DNA repair synthesis on plasmid DNA platinated by photoactivated 1 was markedly lower than for cisplatin or its isomer transplatin (an inactive complex). Single-cell electrophoresis experiments also demonstrated that the DNA damage is different from that induced by cisplatin or transplatin. Cell death is not solely dependent on activation of the caspase 3 pathway, and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of 1. The trans diazido Pt-IV complex 1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy
Unusual DNA binding modes for metal anticancer complexes
No full textDNA is believed to be the primary target for many metal-based drugs. For example, platinum-based anticancer drugs can form specific lesions on DNA that induce apoptosis. New platinum drugs can be designed that have novel modes of interaction with DNA, such as the trinuclear platinum complex BBR3464. Also it is possible to design inert platinum(IV) pro-drugs which are non-toxic in the dark, but lethal when irradiated with certain wavelengths of light. This gives rise to novel DNA lesions which are not as readily repaired as those induced by cisplatin, and provides the basis for a new type of photoactivated chemotherapy. Finally, newly emerging ruthenium(II) organometallic complexes not only bind to DNA coordinatively, but also by H-bonding and hydrophobic interactions triggered by the introduction of extended arene rings into their versatile structures. Intriguingly osmium (the heavier congener of ruthenium) reacts differently with DNA but can also give rise to highly cytotoxic organometallic complexes
The Contrasting Chemistry and Cancer Cell Cytotoxicity of Bipyridine and Bipyridinediol Ruthenium(II) Arene Complexes
No full textThe synthesis and characterization of ruthenium(II) arene complexes [(η6-arene)Ru(N,N)Cl]0/+, where N,N = 2,2′-bipyridine (bipy), 2,2′-bipyridine-3,3′-diol (bipy(OH)2) or deprotonated 2,2′-bipyridine-3,3′-diol (bipy(OH)O) as N,N-chelating ligand, arene = benzene (bz), indan (ind), biphenyl (bip), p-terphenyl (p-terp), tetrahydronaphthalene (thn), tetrahydroanthracene (tha) or dihydroanthracene (dha), are reported, including the X-ray crystal structures of [(η6-tha)Ru(bipy)Cl][PF6] (1), [(η6-tha)Ru(bipy(OH)O)Cl] (2) and [(η6-ind)Ru(bipy(OH)2)Cl][PF6] (8). Complexes 1 and 2 exibit CH (arene)/π (bipy or bipy(OH)O) interactions. In the X-ray structure of protonated complex 8, the pyridine rings are twisted (by 17.31°). In aqueous solution (pH = 2−10), only deprotonated (bipy(OH)O) forms are present. Hydrolysis of the complexes was relatively fast in aqueous solution (t1/2 = 4−15 min, 310 K). When the arene is biphenyl, initial aquation of the complexes is followed by partial arene loss. Complexes with arene = tha, thn, dha, ind and p-terp, and deprotonated bipyridinediol (bipy(OH)O) as chelating ligands, exhibited significant cytotoxicity toward A2780 human ovarian and A549 human lung cancer cells. Complexes [(η6-bip)Ru(bipy(OH)O)Cl] (7) and [(η6-bz)Ru(bipy(OH)O)Cl] (5) exhibited moderate cytotoxicity toward A2780 cells, but were inactive toward A549 cells. These activity data can be contrasted with those of the parent bipyridine complex [(η6-tha)Ru(bipy)Cl][PF6] (1) which is inactive toward both A2780 ovarian and A549 lung cell lines. DFT calculations suggested that hydroxylation and methylation of the bipy ligand have little effect on the charge on Ru. The active complex [(η6-tha)Ru(bipy(OH)O)Cl] (2) binds strongly to 9-ethyl-guanine (9-EtG). The X-ray crystal structure of the adduct [(η6-tha)Ru(bipy(OH)O)(9-EtG-N7)][PF6] shows intramolecular CH (arene)/π (bipy(OH)O) interactions and DFT calculations suggested that these are more stable than arene/9-EtG π−π interactions. However [(η6-ind)Ru(bipy(OH)2)Cl][PF6] (8) and [(η6-ind)Ru(bipy)Cl][PF6] (16) bind only weakly to DNA. DNA may therefore not be the major target for complexes studied here
The Contrasting Chemistry and Cancer Cell Cytotoxicity of Bipyridine and Bipyridinediol Ruthenium(II) Arene Complexes
No full textThe synthesis and characterization of ruthenium(II) arene complexes [(η6-arene)Ru(N,N)Cl]0/+, where N,N = 2,2′-bipyridine (bipy), 2,2′-bipyridine-3,3′-diol (bipy(OH)2) or deprotonated 2,2′-bipyridine-3,3′-diol (bipy(OH)O) as N,N-chelating ligand, arene = benzene (bz), indan (ind), biphenyl (bip), p-terphenyl (p-terp), tetrahydronaphthalene (thn), tetrahydroanthracene (tha) or dihydroanthracene (dha), are reported, including the X-ray crystal structures of [(η6-tha)Ru(bipy)Cl][PF6] (1), [(η6-tha)Ru(bipy(OH)O)Cl] (2) and [(η6-ind)Ru(bipy(OH)2)Cl][PF6] (8). Complexes 1 and 2 exibit CH (arene)/π (bipy or bipy(OH)O) interactions. In the X-ray structure of protonated complex 8, the pyridine rings are twisted (by 17.31°). In aqueous solution (pH = 2−10), only deprotonated (bipy(OH)O) forms are present. Hydrolysis of the complexes was relatively fast in aqueous solution (t1/2 = 4−15 min, 310 K). When the arene is biphenyl, initial aquation of the complexes is followed by partial arene loss. Complexes with arene = tha, thn, dha, ind and p-terp, and deprotonated bipyridinediol (bipy(OH)O) as chelating ligands, exhibited significant cytotoxicity toward A2780 human ovarian and A549 human lung cancer cells. Complexes [(η6-bip)Ru(bipy(OH)O)Cl] (7) and [(η6-bz)Ru(bipy(OH)O)Cl] (5) exhibited moderate cytotoxicity toward A2780 cells, but were inactive toward A549 cells. These activity data can be contrasted with those of the parent bipyridine complex [(η6-tha)Ru(bipy)Cl][PF6] (1) which is inactive toward both A2780 ovarian and A549 lung cell lines. DFT calculations suggested that hydroxylation and methylation of the bipy ligand have little effect on the charge on Ru. The active complex [(η6-tha)Ru(bipy(OH)O)Cl] (2) binds strongly to 9-ethyl-guanine (9-EtG). The X-ray crystal structure of the adduct [(η6-tha)Ru(bipy(OH)O)(9-EtG-N7)][PF6] shows intramolecular CH (arene)/π (bipy(OH)O) interactions and DFT calculations suggested that these are more stable than arene/9-EtG π−π interactions. However [(η6-ind)Ru(bipy(OH)2)Cl][PF6] (8) and [(η6-ind)Ru(bipy)Cl][PF6] (16) bind only weakly to DNA. DNA may therefore not be the major target for complexes studied here
