| 1. |
- Alshiekh, Alak, et al.
(författare)
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Kinetics of cisplatin binding to short r(GG) containing miRNA mimics - influence of Na(+)versus K(+), temperature and hydrophobicity on reactivity.
- 2015
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Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9234 .- 1477-9226. ; 44:28, s. 12623-12632
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Tidskriftsartikel (refereegranskat)abstract
- Nucleic acids are well recognized targets for platinum-based anticancer drugs, with RNA and DNA being kinetically comparable. In the case of RNA, previous studies have shown that the reaction between small duplex RNAs (dsRNAs) and monoaquated cisplatin (cis-Pt(NH3)2Cl(OH2)(+), ) can be followed by the metal induced hyperchromicity occurring directly after addition of to e.g. microRNA mimics. In the present study, we have used this approach to compare thermal stability and reactivity between intracellularly- and extracellularly relevant salt concentration (CNa(+) and CK(+)ca. 0.1 M), and also as a function of increased hydrophobicity (10% v/v EtOH). In addition, reactivity was studied as a function of temperature in the interval ca. 5-20 °C below the respective dsRNA melting temperatures (Tms). Four different 13- to 20-mer dsRNAs with two different central sequence motifs were used as targets containing either a central r(GG)·r(CC)- or r(GG)·r(UAU)-sequence. The reactions exhibited half-lives in the minute- to hour range at 38 °C in the presence of excess in the μM range. Further, a linear dependence was found between C and the observed pseudo-first-order rate constants. The resulting apparent second-order rate constants were significantly larger for the lower melting r(GG)·r(UAU)-containing sequences compared with that of the fully complementary ones; the higher and lower reactivities represented by RNA-1-3 and RNA-1-1 with k2,appca. 30 and 8 M(-1) s(-1) respectively at CNa(+) = 122 mM. For all RNAs a common small, but significant, trend was observed with increased reactivity in the presence of K(+) compared with Na(+), and decreased reactivity in the presence of EtOH. Finally, the temperature dependence of k2,app was evaluated using the Eyring equation. The retrieved activation parameters reveal positive values for both ΔH(≠) and ΔS(≠) for all dsRNAs, in the range ca. 23-34 kcal mol(-1) and 22-57 cal K(-1) mol(-1) respectively. These values indicate solvational effects to be important for the rate determining step of the reaction, and thus in support of a structural change of the dsRNA to take place in parallel with the adduct formation step.
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| 2. |
- Bjelosevic, Haris, et al.
(författare)
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Platinum(II) and gold(I) complexes based on 1,1 '-bis(diphenylphosphino)metallocene derivatives: Synthesis, characterization and biological activity of the gold complexes
- 2012
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Ingår i: Journal of Organometallic Chemistry. - : Elsevier BV. - 0022-328X. ; 720, s. 52-59
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis of series of 1,2,1' substituted bis(diphenylphosphino)- ruthenocenyl (1-4) and ferrocenyl cis-platinum(II) (5-7) and gold(I) (8-12) complexes are described. Crystal structures of 2 and 4, as well as 5, 6 and 10 confirm the molecular geometry of these ligands and their metal complexes. Preliminary investigation of four gold complexes as potential anticancer, antiHIV and antimalaria showed at least one gold compound that has excellent activity towards one of these diseases. The three gold(I) complexes, {1- [1-(dimethylamino)ethyl]-1 ,2-bis(diphenylphosphino)ruthenocene-kappa P-2,P'}bis[chlorogold(I)] (8) (IC50 = 1.40 mu M), {1-[1-(acetoxyethyl)-1',2-bis(diphenylphosphino)ferrocene-kappa P-2,P']bis[chlorogold(1)] (9) (IC50 = 0.51 mu M), {1-[1-(3-carboxypropanamido)ethyl]-1',2-bis(diphenylphosphino)-ruthenocene kappa P-2,P'} bis[chlorogold(I)] (12) (IC50 = 1.784 mu M), have the best activities against cancer, HIV and malaria respectively. (C) 2012 Elsevier B.V. All rights reserved.
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| 3. |
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| 4. |
- 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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| 5. |
- Brindell, Malgorzata, et al.
(författare)
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Light-Induced Anticancer Activity of [RuCl2(DMSO)4] Complexes
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 48:23, s. 7298-7304
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Tidskriftsartikel (refereegranskat)abstract
- The cytotoxicity and photocytotoxicity of trans-[RuCl2(DMSO)4] and cis-[RuCl2(DMSO)4] complexes was tested in two melanoma cell lines, human (SK-MEL 188) and mouse (S91). The trans isomer was found to be more effective for cell growth inhibition than its cis analogue both in the presence and in the absence of illumination. However, the antiproliferative activity of both isomers was significantly enhanced after irradiation with UVA light in comparison with their activity observed in the dark. The influence of light on the reaction of both ruthenium(II) isomers with the single-stranded hexanucleotide d(T2GGT2), chosen as a model system for DNA, was also studied using chromatography and mass spectrometry techniques. The photochemical reaction of the ruthenium(II) complexes with the oligonucleotide d(T2GGT2) resulted in the formation of Ru(G-N7)2 adducts, which was not observed in the same time scale in thermal reactions. The initial short irradiation of the inert cis isomer was found to facilitate the covalent adduct formation with d(T2GGT2) in the secondary thermal reactions and with a rate comparable to that found for the trans isomer, which is ca. 5-10 times more reactive in the dark.
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| 6. |
- Brindell, M, et al.
(författare)
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Mechanistic information on the reaction of cis- and trans-[RuCl2(DMSO)(4)] with d(T(2)GGT(2)) derived from MALDI-TOF and HPLC studies
- 2004
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 98:8, s. 1367-1377
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Tidskriftsartikel (refereegranskat)abstract
- Reactions of trans and cis isomers of the Ru-II complex [RuCl2(DMSO)(4)] with single-stranded hexanucleotide d(T(2)GGT(2)) were studied in aqueous solutions in the absence and presence of excess chloride by high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF MS). Despite the different reactive species formed from the two isomers in aqueous solution, similar reaction products are obtained in their interaction with d(T(2)GGT(2)). Both [RuCl2(DMSO)(4)] isomers bind to the oligonucleotide in the bidentate mode to form thermodynamically stable bis-guanosine adducts, Ru(G-N7)(2), Significant differences were observed in the reaction rates, however the reaction with trans[RuCl2(DMSO)(4)] is ca. 5-10 times faster in comparison to that observed for the cis analogue. This difference is interpreted in terms of different rate-limiting steps for the trans and cis complexes, respectively. It is suggested that the rate of the reaction with the trans isomer is controlled by dissociation of a Cl- ligand from the initially formed trans, cis, cis-[RuCl2(DMSO)(2)(H2O)(2)]. In the contrast, release of a dimethyl sulfoxide molecule from the reactive species cis,fac-[RuCl2(DMSO)(3)(H2O)] is likely to be rate limiting for the cis analogue. Significant influence of electrostatic interactions on the reaction rate was observed for the trans isomer. Mechanistic interpretation of the observed reactivity trends based on data obtained from UV-Vis spectroscopy, HPLC and MALDI-TOF MS studies is presented and discussed within the paper.
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| 7. |
- Damian, Mariana S., et al.
(författare)
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Synthesis and DNA Interaction of Platinum Complex/Peptide Chimera as Potential Drug Candidates
- 2010
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Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X. ; :32, s. 6161-6170
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Tidskriftsartikel (refereegranskat)abstract
- Modification and optimization of the anticancer drug cisplatin is of interest with respect to selective cell targeting and DNA binding efficiency. Attractive approaches contain both, modification of the platinum coordination sphere and design of hybrid molecules of the cisplatin binding moiety including peptide motifs. Peptides with cell penetrating, directing or recognizing properties can be implemented. In this study, positively charged peptide sequences were investigated with the potential of inducing DNA structural distortions caused by charge neutralization of the dsDNA helix. Association of charged peptides is likely to increase the flexibility of the DNA thereby facilitating platinum binding. The synthesis and DNA interaction of five new cisplatin-peptide hybrids with enhanced solubility and potential antitumor activity is presented. Propylenediamine or bisimidazole units were used as bisdentate platinum ligands and were coupled to a peptide sequence in the final elongation step of the solid-phase peptide synthesis (SPPS). Agarose and polyacrylamide gel electrophoresis, fluorescence intercalation, and thermal UV melting studies, all support the presence of covalently formed platinum DNA adducts in a reaction mediated by the positively charged peptide.
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| 8. |
- Elmroth, Sofi, et al.
(författare)
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High-Pressure Stopped-Flow Study of Kinetics and Mechanism for Complex Formation Reactions of Tetraaquapalladium(II) and -Platinum(II) with Thioethers in Aqueous Solution
- 1992
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 1520-510X .- 0020-1669. ; 31:17, s. 3551-3554
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Tidskriftsartikel (refereegranskat)abstract
- Complex formation between Pd(H2O)42+ and Pt(H2O)42+ and the thioethers Me2S, Et2S, 1,4-dithiane, and 1,4-thioxane has been studied as a function of temperature (278-308 K) and pressure (0.1-200 MPa) by use of stopped-flow and conventional spectrophotometry in an aqueous 1.00 M perchloric acid medium. The rate constants k1 for complex formation are similar for the four thioethers, varying only between 1.02 X 10(4) and 3.78 X 10(4) M-1 s-1 for Pd(H2O)42+ and between 0.37 and 0.90 M-1 s-1 for Pt(H2O)42+ at 25-degrees-C. This indicates that changes in size, bulkiness, and solvation of the thioethers have only little importance regarding their properties as entering ligands for these sterically unhindered tetraaqua complexes. The higher rate observed for Pd(II) is mainly an enthalpy effect, and DELTA-H(double dagger) is 38 +/- 6 kJ mol-1 for the reactions with Pd(H2O)42+ and 56 +/- 6 kJ mol-1 for those with Pt(H2O)42+. The reactivity ratio k1Pd/k1Pt is only ca. 4 x 10(4) for the thioethers compared to ca. 10(6) for hard ligands, indicating that the substitution rates of Pt(II) complexes are more sensitive to the nature of the entering ligand than those of Pd(II), as expected for a softer metal center. The rates of the complex formation reactions are similar to the exchange rates of thioethers on the corresponding tetrasolvated thioether cations in the case of Pt(II), in spite of the large trans effects present in the tetrasolvated thioether cations. For Pd(II), the complex formation reactions are even faster than the corresponding thioether-exchange reactions. The comparatively high rates of the complex formation reactions indicate that, in addition to steric factors, changes in relative trans effects as well as effects of bond breaking are important in the activation process for both the exchange and complex formation reactions. Activation volumes are -4.0 +/- 0.2, -8.7 +/- 0.1, -6.6 +/- 0.2, and -10.1 +/- 0.3 cm3 mol-1 for reactions between Me2S, Et2S, S(CH2)4O, and S(CH2)4S and Pd(H2O)42+, respectively, and -15.3 +/- 0.4, -17.0 +/- 0.3, -13.9 +/- 0.3, and -20.1 +/- 0.2 cm3 mol-1 for the Pt(H2O)42+ reactions. These volumes are comparable in size to the activation volumes for thioether exchange on the tetra-coordinated thioether cations. Thus, neither the size or the steric requirements of the ligand nor the steric hindrance of the first coordination sphere of the complex can be used to predict the values of DELTA(double dagger) V in these systems.
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| 9. |
- Elmroth, Sofi K. C., et al.
(författare)
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Competitive Substitution and Electron Transfer in Reactions between Haloamminegold(III) and Halocyanoaurate(III) Complexes and Thiocyanate
- 1996
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 1520-510X .- 0020-1669. ; 35:8, s. 2337-2342
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Tidskriftsartikel (refereegranskat)abstract
- SynopsisReduction of gold(III) complexes by thiocyanate takes place via rapid substitutions at gold(III), followed by intramolecular, slower reductive elimination through attack by outer-sphere thiocyanate. A transition state with an S−S interaction between attacking and coordinated thiocyanate is suggested for the redox process.AbstractAbstract ImageKinetics for reactions between thiocyanate and trans-Au(CN)2Cl2-, trans-Au(CN)2Br2-, and trans-Au(NH3)2Cl2+ in an acidic, 1.00 M perchlorate aqueous medium have been studied by use of conventional and diode-array UV/vis spectroscopy and high-pressure and sequential-mixing stopped-flow spectrophotometry. Initial, rapid formation of mixed halide−thiocyanate complexes of gold(III) is followed by slower reduction to Au(CN)2- and Au(NH3)2+, respectively. This is an intermolecular process, involving attack on the complex by outer-sphere thiocyanate. Second-order rate constants at 25.0 °C for reduction of trans-Au(CN)2XSCN- are (6.9 ± 1.1) × 104 M-1 s-1 for X = Cl and (3.1 ± 0.7) × 103 M-1 s-1 for X = Br. For reduction of trans-Au(CN)2(SCN)2- the second-order rate constant at 25.0 °C is (3.1 ± 0.1) × 102 M-1 s-1 and the activation parameters are ΔH⧧ = (55 ± 3) × 102 kJ mol-1, ΔS⧧ = (−17.8 ± 0.8) J K-1 mol-1, and ΔV⧧ = (−4.6 ± 0.5) cm3 mol-1. The activation volume for substitution of one chloride on trans-Au(NH3)2Cl2+ is (−4.5 ± 0.5) cm3 mol-1, and that for reduction of trans-Au(NH3)2(SCN)2+ (4.6 ± 0.9) cm3 mol-1. The presence of π-back-bonding cyanide ligands stabilizes the transition states for both substitution and reductive elimination reactions compared to ammine. In particular, complexes trans-Au(CN)2XSCN- with an unsymmetric electron distribution along the X−Au−SCN axis are reduced rapidly. The observed entropies and volumes of activation reflect large differences in the transition states for the reductive elimination and substitution processes, respectively, the former being more loosely bound, more sensitive to solvational changes, and probably not involving any large changes in the inner coordination sphere. A transition state with an S−S interaction between attacking and coordinated thiocyanate is suggested for the reduction. The stability constants for formation of the very short-lived complex trans-Au(CN)2(SCN)2- from trans-Au(CN)2X(SCN)- (X = Cl, Br) by replacement of halide by thiocyanate prior to reduction can be calculated from the redox kinetics data to be KCl,2 = (3.8 ± 0.8) × 104 and KBr,2 = (1.1 ± 0.4) × 102.
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| 10. |
- Elmroth, Sofi K.C., et al.
(författare)
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Kinetics and Mechanism for Reaction between Ammine- and Haloamminegold(III) Complexes and Thiocyanate. Competitive Electron Transfer and Substitution
- 1989
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 1520-510X .- 0020-1669. ; 28:14, s. 2703-2710
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Tidskriftsartikel (refereegranskat)abstract
- The reactions in acidic aqueous solution between thiocyanate and each of the gold(III) complexes Au(NH3)43+, trans-Au(NH3)2C12+, and trans-Au(NH3)2Br2+ have been studied by use of potentiometric pH measurements and sequential-mixing stopped-flow spectrophotometry. The reactions give a common gold(I) product whereas the rate-controlling steps are different. The reaction between Au(NH3)43+ and thiocyanate takes place via rate-controlling substitution of an ammine ligand by thiocyanate with k = 7.6 +- 0.1 M-I s-l, DeltaHo = 61+- 1 kJ mol-I, and DeltaSo= 26+-3 J mo1-1 K-1 at 25.0 "C, followed by rapid reduction to gold(1) with the overall stoichiometry 3Au(NH3)43+ + 6SCN- + 4H+ + 4H20 = 2Au(SCN)2- + Au(SCN)(CN)- + S042- + 12NH4+ (i)For trans-Au(NH3)2X2+ (X = CI, Br), thiocyanate replaces halide in two rapid consecutive and reversible substitution steps without an observable solvent path prior to the slower reduction: trans-Au(NH3)2X2+ = Au(NH3)2XSCN+ = trans-Au(NH3)2(SCN)2+ (ii) Second-order rate constants (M-I s-I) at 2.0 oC are as follows: for X = CI; k1 = (9.0+-1.4) x I03, k-1 = (0.6+-0.2), k2 = (1.56+-0.21) X I05, k-2 = (3.4+-0.6) x 102; for X = Br, k1= (8.9+-0.3) x 104, k-1 = (1.32+-0.20) x 103, k2 = (1.4+-0.4) x 105, k-2 = (1.0+-0.7) x 104. Temperature variation of k, gave the following values: for X = CI; DeltaHo = 33+-7 kJ mol-', DeltaSo = -48+-21 J K-1 mol-1; for X = Br, DeltaHo = 30+-11 kJ mol-1, deltaSo = -50+-30 J K-1 mo1-1 at 25.0 oC. Parametrization of the substitution rate constants shows that the nature of the entering ligand is even more important than the trans effect for these complexes, in marked contrast to isoelectronic Pt(II) complexes. The relative stability constants for these short-lived complexes, K, = k,/k,, were obtained from the rate constants and are as follows: for X = CI, K1 = (1.5+-0.5) X 104, K2 = (4.6+-0.5) X 102; for X = Br, K1 = 67+-12, K2 = 12+-3. The ratio KI/K2 shows a nonstatistical distribution for the chloro-thiocyanato system, indicating a increased thermodynamic stability for the complex trans-Au(NH3)2CISCN+, whereas the bromo-thiocyanato system is approximately statistically distributed. An UV-vis spectrum for the intermediate short-lived complex trans-Au(NH3)2BrSCN+ was calculated from continuous-flow spectra. Reduction to gold(1) takes place via three parallel paths subsequent to establishment of the rapid substitution equilibria (ii). Each gold(III) complex trans-Au(NH3)2X(2-n)(SCN)n+ is reduced by outer-sphere thiocyanate in second-order reactions. The second-order rate constants, krn (n = 0, 1, 2), at 25.0 oC are as follows: for X = CI, kr1 = (2.7+-0.5) x 103, kr2 = (2.2+-0.4) x 102; for X = Br, kr0 = 10+-5, kr1 = (3.0+-0.5) x 102, kr2 = (2.5+-0.4) x 102 M-1 s-1, Temperature variation of kr2 gave DeltaHo = 66+-4 kJ mol-1 and DeltaSo = 21+-12 J mol-1 K-1 at 25.0 oC. The mixed chloro- and bromo-thiocyanato complexes are reduced most rapidly, indicating that an asymmetric distribution of electrons along the trans-axis facilitates reduction. It is concluded that reduction takes place by attack of outer-sphere thiocyanate on the sulfur of a coordinated thiocyanate. In keeping herewith, the two complexes trans-Au(NH3)2XSCN' (X = CI, Br), which contain a loosely bound halide ligand in the ground state, also substitute this halide ligand for thiocyanate most rapidly (k2). A unified mechanism for competitive electron transfer and ligand substitution for the reaction between gold(III) complexes and reducing ligands is suggested
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