{1-[1-(3-Carboxy­propanamido)eth­yl]-1′,2-bis­(diphenyl­phosphino)ferrocene-κ2 P,P′}dichloridoplatinum(II) dichloro­methane 1.25-solvate

The dinuclear title compound, [FePtCl2(C17H14P)(C23H23NO3P)]·1.25CH2Cl2, has a slightly distorted cis-PtCl2P2 square-planar geometry around the Pt atom, and the ferrocenylphosphine ligands are staggered at an angle of 29.4 (2)° about Pt. In the crystal structure, the complex forms centrosymmetric dimers via two strong inter­molecular O—H⋯O bonds resulting in R 2 2(8) rings. A weak intra­molecular N—H⋯Cl bond leads to an S(8) motif. The solvent is highly disordered and has not been modelled with discrete atoms

Kinetics and mechanism for platination of thione-containing nucleotides and oligonucleotides: evaluation of the salt dependence

Reactions of cis-[PtCl(NH3)(CyNH2)(OH2)](+) (Cy = cyclohexyl) with thione-containing single-stranded oligonucleotides d(T8XT8) and d(XT16) (X = I-s6 or U-s4) and the mononucleotides 4-thiouridine ((UMP)-U-s4) and 6-mercaptoinosine ((IMP)-I-s6) have been studied in aqueous solution at pH 4.1. The reaction kinetics was followed using HPLC methodology as a function of ionic strength in the interval 5.0 mM less than or equal to I less than or equal to 300 mM. A two-fold kinetic preference for reaction with the I-s6 moiety over U-s4 is observed in both monomeric and oligomeric systems. The rate for adduct formation with the oligonucleotides d(T8XT8) and d(XT16) decreases with increasing ionic strength of the medium. The effect is most pronounced for adduct formation with the middle positions, e.g. for d((T8IT8)-I-s6): k(2,app) = 130 M-1 s(-1) and 13 M-1 s(-1) at I = 5.0 and 300 mM, respectively, and slightly less pronounced for adduct formation at the end positions, e.g. for d((IT16)-I-s6): k(2,app) = 130 M-1 s(-1) and 11 M-1 s(-1) at I = 5.0 and 300 mM, respectively. Analysis of the salt dependence using the Bronsted-Debye-Huckel relationship shows that the reactions with the monomers are well described as an interaction between a monovalent cation and a monovalent anion. In contrast, a similar analysis of the oligonucleotide reactions indicates influence from polyelectrolyte effects. The results support a mechanism in which pre-association on the DNA surface precedes adduct formation, regardless of the exact location of the final binding site

Similar rates for platination of hairpin loops and single-stranded DNA

The presence of ribonucleic acid hairpin structures is important for proper processing of the genetic information in living cells. Recent studies indicate that interactions between platinum based anticancer active metal complexes and hairpin motifs result in a change of their three-dimensional structure combined with a decrease of the melting temperature. We here report a study of the reaction between two platinum complexes, cis-[PtCl(NH3)(2)(OH2)](+) I and, cis-[PtCl(NH3)(c-NH2C6H11)(OH2)](+) II, and a series of short DNA hairpins which all exhibit a documented preference for adduct formation with donor groups located in the loop region; d(CGCGTTXTTCGCG), where X = G-N7, p(S), I-s6 or U-s4. The binding kinetics of adduct formation with the hairpins have been compared with that of binding to similar size single-stranded DNA; d(T6XT6), where X = G, p(S), I-s6 or U-s4. The overall picture reveals rather similar reactivity of the platinum complexes towards these two DNA secondary structures. However, the smaller complex I exhibits a tendency for preferential interaction with the hairpins, whereas the more bulky complex II shows a higher reactivity towards the single-stranded structures

Time dependence of cisplatin-induced duplex dissociation of 15-mer RNAs and mature miR-146a.

The kinetics for the binding of cisplatin to duplex RNAs, two fully complementary model systems and mature miR-146a, exhibits a linear dependence on cisplatin concentration and results in duplex dissociation at 38 °C

A comparative kinetic study of modified Pt(dppf)Cl-2 complexes and their interactions with L-cys and L-met

With the success of cisplatin (cis-diamminedichloroplatinum(II)), strong interest has developed in the application of inorganic metal complexes to the treatment of cancer. Research has focused on platinum( II) complexes with a variety of spectator ligands that provide novel physicochemical properties. In this paper we report a kinetic study of 1', 1'-bis(diphenylphosphino) ferrocenedichloroplatinum( II) and two related compounds with either an acetate or amide ester substituent attached to the cyclopentadienyl ring. For all compounds the reactivity towards L-cysteine and L-methionine in aqueous solution has been investigated (25 degrees C, I = 0.010 M and pseudo-first-order conditions). For the reactions with L-cysteine and L-methionine the reactions proceeded via a steady-state aquated intermediate to form mono (0.92(2) - 3.25( 4)) x 10(-3) s(-1)) and bis adducts (0.97( 2) - 3.67(4)) x 10(-4) s(-1)). For reactions with L- cysteine, direct reactions with the starting complex also contributed ( mono adduct: 0.36( 2) - 1.41(4) M-1 s(-1), bis adduct: 0.080(1) - 0.96(1) M-1 s(-1)). The attached substituents were found to have a significant effect upon the reaction kinetics, with the substituted complexes found to have increased reactivity. It is proposed that the increased reactivity stems from hydrogen bonding between the substituent and the entering ligand and subsequent outer-sphere complex stabilisation. Evidence in support of this theory was obtained form measurements in dichloromethane with 1-propanethiol as the entering ligand. The reactivity of the dppf containing complexes was also compared to that of cisplatin ( mono adduct: (0.170( 1) - 0.175(1)) x 10(-3) s(-1), bis adduct: (0.183( 1) - 0.397( 1)) x 10(-4) s(-1)) and found to be significantly enhanced

Expanding the chemical nature of siRNAs: Oxaliplatin as metalation reagent.

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

Platination of the siRNA sense-strand modulates both efficacy and selectivity in vitro

The use of short interfering RNAs (siRNA) for selective suppression of protein production has rapidly become a commonly used technique for transient modulation of protein levels. In the present paper, we investigate whether introduction of platinated bases in the sense strand can be used to modulate the efficacy of siRNAs. Four different siRNAs were studied, all targeting the initial AU-rich 3' UTR of Wnt-5a mRNA. The siRNAs were characterized with respect to melting properties and translational inhibitory effect in vitro using luciferase as a reporter gene. The translation inhibition studies reveal that all platinated siRNA remain efficient. For an siRNA with partial complementarity to the lucifierase gene, platination was shown to reduce the off-target effects. All siRNAs were found to be active in cellular in vitro translation systems, reaching suppression levels well above 80% for the majority of siRNAs investigated. (c) 2007 Elsevier Inc. All rights reserved

Kinetics of cisplatin binding to short r(GG) containing miRNA mimics - influence of Na(+)versus K(+), temperature and hydrophobicity on reactivity.

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