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| 2. |
- Bjelosevic, Haris, et al.
(författare)
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Synthesis and structural characterisation of novel platinum-based drug candidates with extended functionality by incorporation of bis(diphenylphosphino)ferrocene units as metal chelators
- 2006
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 62:18, s. 4519-4527
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Tidskriftsartikel (refereegranskat)abstract
- Among the metal-based anticancer drugs, cisplatin (cis-diaminedichloroplatinum(II)) is the most widely used species in therapy. Despite its clinical success, cisplatin still suffers in generating resistance, as well as being highly toxic due to poor selectivity between healthy and sick cells. By molecular design it ought to be possible to generate new cis-platinum compounds with increased selectivity and improved cellular behaviour. In this paper, we report a synthetic pathway for construction of derivatives of 1,1'-bis(diphenylphosphino)-ferrocene, together with their corresponding cis-platinum compounds with the aim testing them for their interaction capacity with respect to various DNA models. We also report a synthetic route for a nucleoside-based cis-platinum compound containing a bidentate ferrocenylphosphine derivative connected through a succinamic-based linker to the 5-position of the heterocyclic moiety of uridine. Our preliminary kinetic investigation of 5-{N-[1-[1',2-bis(diphenylphosphino)ferrocenyl]ethyl]1-N'-[prop-2-yn-3-y l]succinamide} uridinedichloroplatinum(II) showed that this compound reacted faster with the phosphorothioate containing oligonucleotides d(T(6)p(S)T-6), with an observed first-order rate constant k(obs) = (1.4 +/- 0.1) X 10(-4) s(-1), compared with the G-N7 target in d(T(7)GGT(7)), for which the observed first-order rate constant is k(obs) = (7.2 +/- 0.5) X 10(-4) s(-1). (c) 2006 Elsevier Ltd. All rights reserved.
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| 3. |
- Papsai, Pal, et al.
(författare)
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Platination of full length tRNA(Ala) and truncated versions of the acceptor stem and anticodon loop.
- 2008
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234 .- 1477-9226. ; :38, s. 5225-5234
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear DNA is a well characterized target for many low molecular metal-based drugs, with cisplatin and related antineoplastic compounds as typical examples. Much less is known concerning to what extent targeting of RNA may influence the activity spectrum of these types of drugs. In a preliminary communication by us (Papsai et al., Dalton Trans., 2006, 3515) we were able to show that the folded, three-dimensionally well defined structure of tRNA(Ala) readily interacts with cisplatin. In the present study we have further analyzed the binding preferences within the preferentially targeted stem region (sMh(Ala)) by modulation of the sequence around the G-U wobble base-pair and the net charge of the 3' and 5' ends. Our data show that the adduct profile is strongly influenced by the presence of the 5' end phosphate group. Further, the adduct formation reaction can be prevented by replacement of the G-U wobble base-pair with the fully complementary G-C pair. To further investigate the influence from local sequence on the platination process, a model of the anticodon region (acMh(Ala)) was also investigated. In the absence of consecutive guanine-residues in the stem- and anticodon regions, preferential platination was found to take place at the terminal AG-site in the stem region. However, after introduction of a GG-pair in the anticodon loop, platination was observed also here. At 37 degrees C, pH 6.3 and C(Pt) = 0.10 mM the rate of platination was determined to be ca. 1 x 10(-4) s(-1), with the most rapid reaction observed for interaction with the anticodon model carrying two adjacent guanines in the single-stranded loop. Together, these data show that platination of RNA is highly sequence- and structure-dependent.
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| 4. |
- Snygg, Åse Sykfont, et al.
(författare)
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A combination of access to preassociation sites and local accumulation tendency in the direct vicinity of G-N7 controls the rate of platination of single-stranded DNA
- 2005
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234 .- 1477-9226. ; 2005, s. 1221-1227
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Tidskriftsartikel (refereegranskat)abstract
- Adduct formation between cationic reagents and targets on DNA are facilitated by the ability of DNA to attract cations to its surface. The electrostatic interactions likely provide the basis for the documented preference exhibited by cisplatin and related compounds for nuclear DNA over other cellular constituents. As an extension of a previous communication, we here present an investigation illustrating how the rate of adduct formation with the naturally occuring base guanine (G-N7) can be modulated by i) bulk solvent conditions, ii) local nature and size of the surrounding DNA and, iii) increasing DNA concentration. A series of single-stranded DNA oligomers of the type d(TnGTm); n= 0, 2, 4, 6, 8, 10, 12, 14, 16 and m= 16 –n or n=m= 4, 6, 8, 12, 16, 24 were allowed to react with the active metabolite of a potential orally active platinum(IV) drug, cis-[PtCl(NH3)(c-C6H11NH2)(OH2)]+ in the presence of three different bulk cations; Na+, Mg2+, and Mn2+. For all positions along the oligomers, a change from monovalent bulk cations to divalent ones results in a decrease in reactivity, with Mn2+ as the more potent inhibitor as exemplified by the rate constants determined for interaction with d(T8GT8): 103×kobs/s–1= 6.5 ± 0.1 (Na+), 1.8 ± 0.1 (Mg2+), 1.0 ± 0.1 (Mn2+) at pH 4.2 and 25 °C. Further, the adduct formation rate was found to vary with the exact location of the binding site in the presence of both Na+ and Mg2+, giving rise to reactivity maxima at the middle position. Increasing the size of the DNA-fragments was found to increase the reactivity only up to a total length of ca. 20 bases. The influence from addition of further bases to the reacting DNA was found to be salt dependent. At [Na+]= 0.5 mM a retardation in reactivity was observed whereas [Na+] 4.5 mM give rise to length independent kinetics. Finally, for the first time we have here been able to evaluate the influence from an increasing concentration of non-reactive DNA bases on the adduct formation process. The latter data were successfully fitted to an inhibition model suggesting that non-productive association of the platinum complex with sites distant from G-N7 competes with productive ones in the vicinity of the G-N7 target. Taken together, the kinetics support a reaction mechanism in which access to suitable association sites in the direct vicinity of the target site controls the rate of platination.
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| 5. |
- Sykfont Snygg, Åse
(författare)
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Cationic Interactions with Nucleic Acids With Focus on Anticancer Active Platinum(II) Complexes
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is well documented that the antitumour activity of the Pt(II)-complex cisplatin, and similar anticancer active complexes, is a result of metalation of DNA, and thereby inhibition of cell proliferation. Since nucleic acids are polyanions at physiological pH, the rate of adduct formation with positively charged complex, as the hydrolyzed Pt(II) complexes studied in this work, is influenced by the ionic environment surrounding the polymer. Such effects have been investigated in different nucleic acid models. The type and concentration of bulk cations highly affect the reaction rate, e.g. divalent ions are more efficient in retarding the platination reaction than monovalent ions, due to the better neutralization of the phosphate charges. The rates of adduct formation between cis-[PtCl(NH3)(c-C6H11NH2)(OH2)]+ and a model with single-stranded oligonucleotides were found to decrease significantly in the presence of manganese(II) in comparison to magnesium(II). This is suggested to be a result of a direct interaction for manganese(II) with the platination site, G-N7. Furthermore, the reactivity was found to depend on the location of the target site within the oligomers, where the central position possessed the highest rate. The influence from the oligomeric length on the reaction rate with cis-[PtCl(NH3)(c-C6H11NH2)(OH2)]+ and d(TnGTn), where n = 4, 6, 8, 12, 16 and 24, was studied. A length-dependent rate enhancement was found up to n = 8, at low concentration of bulk cations. These results present evidence for the presence of a rate enhancing preassociation step in the reaction mechanism. Studies of addition of tri- and tetravalent polyamines to the platination reaction of single stranded oligomers and dsDNA were performed. Results varied on the bulk cation concentration and type of polyamine. The overall trend was a decrease in platination rate in the presence of polyamines. Polyamine competition with the platinum(II) complex for the condensation layer, including direct association with the platination site, was assumed to be responsible for the decreased platination rate. Platination of nucleic acids is known to induce structural distortions, resulting in duplex destabilization and higher rigidity of the structure. Both these effects were separately studied with two different RNA–models. An RNA oligonucleotide with a potential to adopt a pseudoknot structure, was platinated and found to be more stable towards intramolecular transesterification than the unmetalated one. This observation was interpreted as a result of higher rigidity of the whole molecule. The other model used was short duplex RNAs, with function as efficient siRNAs in a model system. Incorporation of oxaliplatin in the sense strand results in duplex destabilization, but with retained efficiency as siRNAs. This is promising for future studies of metalated siRNAs.
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| 6. |
- Sykfont Snygg, Åse, et al.
(författare)
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Expanding the chemical nature of siRNAs: Oxaliplatin as metalation reagent.
- 2009
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 379:2, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Short interfering RNAs (siRNAs) can down-regulate protein production by site specific degradation of mRNA. We here report the in vitro efficiency of three siRNAs metalated with oxaliplatin. All siRNAs were selectively platinated in the sense strand, and designed to target the AU-rich 3' UTR region of Wnt-5a mRNA cloned into a luciferase reporter plasmid. Two of the studied siRNAs reveal luciferase protein suppression levels well above 90% when used in nano-molar concentrations for both metalated and the corresponding native siRNA. The platinated siRNAs were also characterized with respect to thermal melting properties, and the number of platinum adducts on the different sense strands were determined by MALDI-ToF MS. In all cases, platination was accompanied by a decrease in melting temperature. Further, the dominating oxaliplatin metalation site was the r(GpG)-adduct. The study indicates that metalation can be used as a general strategy to further expand the chemical nature of siRNAs.
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| 7. |
- Sykfont Snygg, Åse, et al.
(författare)
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The polyamines spermidine and spermine retard the platination rate of single-stranded DNA oligomers and plasmid
- 2007
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 101:8, s. 1153-1164
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Tidskriftsartikel (refereegranskat)abstract
- The presence of polyamines in living cells is crucial for survival. Due to their high net charge at physiological pH, polyamines effectively charge neutralize the phosphodiester backbone of DNA in an interaction that also may protect the DNA from external damage. We here present a study illustrating the influence of spermidine and spermine on the platination reactions of the model oligonucleotides d(T(6)GT(6)), d(T(12)GT(12)), and d(T(24)GT(24)), and the pUC18 DNA plasmid. The aquated forms of the anticancer active compounds cisplatin (cis-[Pt(NH3,)(2)Cl-2]) and the major Pt(II) metabolite of JM216 (Cis-[PtCl2(NH3)(C-C6H11 NH2)], JM118) were used as platination reagents. The study shows that the kinetics for formation of the coordinative Pt-DNA adduct are strongly influenced by the presence of sub-millimolar polyamine concentrations. At polyamine concentrations in the mu M-range, the reactions remain salt-dependent. In contrast, platination of pUC 18 is effectively prevented at mM concentrations of both spermidine and spermine with the latter as the more potent inhibitor. The results suggest that variations of intracellular polyamine concentrations may have a profound influence on the efficacy by which cationically charged reagents interfere with DNA function in vivo by modulation of the preassociation conditions. (c) 2007 Elsevier Inc. All rights reserved.
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