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B Lippert

Publications and source records attributed to B Lippert.

At least 19 recordsLinked to original sources
PubMed2001

Protonation of platinated adenine nucleobases. Gas phase vs condensed phase picture.

Protonation of adenine carrying a Pt(II) moiety either at N7, N3, or N1 is possible in solution, but the site of protonation is influenced by the location of the Pt(II) electrophile and to some extent also by the overall charge of the metal entity (+2, +1, 0, -1), hence the other ligands (NH(3), Cl(-), OH(-)) bound to Pt(II). Quantum chemical calculations based on density functional theory (DFT) have been carried out for intrinsic protonation energies of adenine complexes carrying the following Pt(II) species at either of the three ring N atoms: [Pt(NH(3))(3)](2+) (1), trans- [Pt(NH(3))(2)Cl](+) (2a), cis-[Pt(NH(3))(2)Cl](+) (2b), trans-[Pt(NH(3))(2)Cl(2)] (3a), cis-[Pt(NH(3))Cl(2)] (3b), [PtCl(3)](-) (4), trans-[Pt(NH(3))(2)OH](+) (5a), cis-[Pt(NH(3))(2)(OH)](+) (5b), trans-[Pt(NH(3))(OH)(2)] (6a), cis-[Pt(NH(3))(OH)(2)] (6b), and [Pt(OH)(3)](-) (7). The data have been compared with results derived from solution studies (water) and X-ray crystallography, whenever available. The electrostatic effects associated with the charge of the metal entity have the major influence on the calculated intrinsic (gas phase) proton affinities, unlike the condensed phase data. Nevertheless, the relative gas phase trends correlate surprisingly well with condensed phase data; i.e., variation of the pK(a) values measured in solution is consistent with the calculated gas phase protonation energies. In addition to a systematic study of the ring proton affinities, proton transfer processes within the platinated adenine species were often observed when investigating Pt adducts with OH(-) ligands, and they are discussed in more detail. To the best of our knowledge, this is the first study attempting to find a systematic correlation between gas phase and condensed phase data on protonation of metalated nucleobases. The gas phase data provide a very useful complement to the condensed phase and X-ray experiments, showing that the gas phase studies are capable of valuable predictions and contribute to our understanding of the solvent and counterion effects on metal-assisted proton shift processes.

Adenine Nucleotides↗
PubMed2001

Metal-modified nucleobase pairs and triplets as cytosine receptors.

A preorganized cationic receptor 2 for cytosine (C) is described which is composed of trans-a2PtII (a= NH3 or CH3NH2) cross-linked modules with adenine (A), guanine (G), and uracil (U) or thymine (T) model nucleobases. The functions of these three modules are as follows: i) Adenine orientates the two other bases at right angles, thus producing the L-shape of the receptor. ii) Guanine is the primary receptor. iii) Uracil or thymine act as coreceptors. Compared with the normal Watson-Crick pair between G and C, the association constant between 2 and C increases by a factor of 3 (in DMSO). As deduced from 1H NMR spectroscopy and confirmed by the X-ray crystal structure of the C adduct 4b, cytosine is fixed through five hydrogen bonds to the receptor, one of which involves the aromatic H(5) of C. A comparison of C binding is made with a structurally related linkage isomer receptor as well as the precursor molecule trans[alpha2PtAG]2+. The potential of modular, cationic receptors is illustrated.

Base Pairing↗
PubMed2001

Formation of ternary complexes by coordination of (diethylenetriamine)-platinum(II) to N1 or N7 of the adenine moiety of the antiviral nucleotide analogue 9.

The synthesis of (Dien)Pt(PMEA-N1), where Dien = diethylenetriamine and PMEA2- = dianion of 9-[2-(phosphonomethoxy)ethyl]adenine, is described. The acidity constants of the threefold protonated H3[(Dien)Pt(PMEA-N1)]3+ complex were determined and in part estimated (UV spectrophotometry and potentiometric pH titration): The release of the proton from the (N7)H+ site in H4[(Dien)Pt(PMEA-N1)]3+ occurs with a rather low pKa (= 0.52+/-0.10). The release of the proton from the -P(O)2(OH) group (pKa = 6.69+/-0.03) in H[(Dien)Pt(PMEA-N1)]+ is only slightly affected by the N1-coordinated (Dien)Pt2+ unit. Comparison with the acidic properties of the H[(Dien)Pt(PMEA-N7)]+ species provides evidence that in the (Dien)Pt(PMEA-N7) complex in aqueous solution an intramolecular, outer-sphere macrochelate is formed through hydrogen bonds between the -PO3(2-) residue of PMEA2- and a PtII-coordinated (Dien)NH2 group; its formation degree amounts to about 40%. The stability constants of the M[(Dien)Pt(PMEA-N1)]2+ complexes with M2+ = Mg2+, Ca2+, Ni2+, Cu2+ and Zn2+ were measured by potentiometric pH titrations in aqueous solution at 25 degrees C and I = 0.1 M (NaNO3). Application of previously determined straight-line plots of log K(M(R-PO3))M versus pK(H(R-PO3)H for simple phosph(on)ate ligands. R-PO3(2-), where R represents a non-inhibiting residue without an affinity for metal ions, proves that the primary binding site of (Dien)Pt(PMEA-N1) is the phosphonate group with all metal ions studied; in fact, Mg2+, Ca2+ and Ni2+ coordinate (within the error limits) only to this site. For the Cu[(Dien)Pt(PMEA-N1)]2+ and Zn[(Dien)Pt(PMEA-N1)]2- systems also the formation of five-membered chelates involving the ether oxygen of the -CH2-O-CH2-PO3(2-) residue could be detected; the formation degrees are about 60% and 30%, respectively. The metal-ion-binding properties of the isomeric (Dien)Pt(PMEA-N7) species studied previously differ in so far that the resulting M[(Dien)Pt(PMEA-N7)]2+ complexes are somewhat less stable, but again Cu2+ and Zn2+ also form with this ligand comparable amounts of the mentioned five-membered chelates. In contrast, both M[(Dien)Pt(PMEA-N1/N7)]2+ complexes differ from the parent M(PMEA) complexes considerably; in the latter instance the formation of the five-membered chelates is of significance for all divalent metal ions studied. The observation that divalent metal-ion binding to the phosphonate group of (Dien)Pt(PMEA-N1) and (Dien)Pt(PMEA-N7) is only moderately inhibited (about 0.2-0.4 log units) by the twofold positively charged (Dien)Pt2+ unit at the adenine residue allows the general conclusion, considering that PMEA is a nucleotide analogue, that this is also true for nucleotides and that consequently participation of, for example, two metal ions in an enzymatic process involving nucleotides is not seriously hampered by charge repulsion.

Adenine↗
PubMed2001

Metal-modified nucleobase sextet: joining four linear metal fragments (trans-a2PtII) and six model nucleobases to an exceedingly stable entity.

Crosslinking of three different model nucleobases (9-ethyladenine, 9-EtA; 9-ethylguanine, 9-EtGH; 1-methyluracil, 1-MeU) by two linear trans-aPtII (a = NH3 or CH3NH2) entities leads to a flat metal-modified base triplet, trans,trans-[(NH3)2Pt(1-MeU-N3)(mu-9-EtA-N7,N1)Pt(CH3NH2)2(9-EtGH-N7)]3+ (4b). Upon hemideprotonation of the 9-ethylguanine base at the N1 position. 4b spontaneously dimerizes to the metalated nucleobase sextet 5, [(4b)(triple bond)(4b-H)]5+. In this dimeric structure a neutral and an anionic guanine ligand, which are complementary to each other, are joined through three H bonds and additionally by two H bonds between guanine and uracil nucleobases. Four additional interbase H bonds maintain the approximate coplanarity of all six bases. The two base triplets form an exceedingly stable entity (KD = 500 +/- 150 M(-1) in DMSO), which is unprecedented in nucleobase chemistry. The precursor of 4b and several related complexes are described and their structures and solution properties are reported.

Base Pairing↗
PubMed2001

Thymine-metal ion interactions: relevance for thymine quartet structures.

Apart from their function as counter ions for the charge neutralization of nucleic acids, alkali metal ions play important roles in stabilizing particular multistranded nucleic acids, e.g. guanine quartets in telomeres and uracil (U) or thymine (T) quartets. Here X-ray crystal structure determinations of a series of alkali metal ions (Na+, K+, Rb+, Cs+) as well as of Mg2+ and H5O2+ adducts with the model bases 1-methylthymine and 1-ethylthymine are reported, which bear relevance to the question of thymine quartet (T4) geometries. The compounds isolated differ in their stoichiometries (T:M = 4:1, 2:1, 1:1), and the ways the metal ions interact with the bases. The two extremes are exclusive metal coordination to exocyclic oxygen atoms of the T bases and exclusive H bonding between M aqua cations and the bases.

Binding Sites↗
PubMed2000

Solid-Phase Synthesis of a Monofunctional trans-a(2)Pt(II) Complex Tethered to a Single-Stranded Oligonucleotide.

Cross-linking ability is possible with the oligonucleotide-tethered, monofunctional trans-Pt(II) complex shown. It was synthesized by a novel solid-phase approach comprising conjugation of immobilized tetrathymidylic acid with a trans-a(2)Pt(II) building unit, ammonolysis, and transformation of the resulting complex (R=1-N-cyclohexylmethylthyminate) into the chloro derivative (R=Cl). a=NH(2)CH(3), T=thymine.

Journal Article↗
PubMed2000

Effects of N7-methylation, N7-platination, and C8-hydroxylation of guanine on H-bond formation with cytosine: platinum coordination strengthens the Watson-Crick pair.

The hydrogen bonding properties of 1-methylcytosine (1-MeC) with the following guanine base derivatives have been studied in DMSO-d6, applying concentration-dependent 1H NMR spectroscopy: 9-ethylguanine, 7,9-dimethylguanine (7,9-DimeGH+), and 7,8-dihydro-8-oxo-9-methylguanine (8-O-9-MeGH), as well as three 9-ethylguanine complexes carrying different Pt(II) moieties at the N7 position. The association constants K for the Watson-Crick pairing schemes are by a factor 2-3 higher in the cases of platinated guanine complexes compared to the Watson-Crick pair between 9-ethylguanine and 1-methylcytosine (K = 6.9 +/- 1.3 M(-1)). Similar enhanced stabilities are observed for the pairs formed between 1-MeC and 7,9-DimeGH+ or 8-O-9-MeGH. The increase in N1H acidity of the guanine derivative upon modification at the N7 or C8 positions can be correlated with the association constants K; the result is a bell-shaped curve meaning that acidification initially stabilizes hydrogen bond formation up to a certain maximum; further acidification then leads to a destabilization. For two of the examples studied in solution, hydrogen bonding according to Watson-Crick between N7-platinated 9-ethylguanine and 1-methylcytosine has also been established by X-ray crystallography.

Crystallography, X-Ray↗
PubMed2000

Parallel-stranded DNA with Hoogsteen base pairing stabilized by a trans-[Pt(NH3)2]2+ cross-link: characterization and conversion into a homodimer and a triplex.

The oligonucleotides 5'-d(TTTTCTTTTG) and 5'-d(AAAAGAAAAG) were cross-linked with a trans-[Pt(NH3)2]2+ entity via the N7 positions of the 3'-end guanine bases to give parallel-stranded (ps) DNA. At pH 4.2, CD and NMR spectroscopy indicate the presence of Hoogsteen base pairing. In addition, temperature-dependent UV spectroscopy shows an increase in melting temperature for the platinated duplex (35 degrees C) as compared to the non-platinated, antiparallel-stranded duplex formed from the same oligonucleotides (21 degrees C). A monomer-dimer equilibrium for the platinated 20mer is revealed by gel electrophoresis. At pH 4.2, addition of a third strand of composition 5'-d(AGCTTTTCTTTTAG) to the ps duplex leads to the formation of a triple helix with two distinct melting points at 38 degrees C (platinum cross-linked Hoogsteen part) and 21 degrees C (Watson-Crick part), respectively.

Base Pairing↗
PubMed2000

Heavy metal mutagenicity: insights from bioinorganic model chemistry.

The mutagenicity of metal species may be the result of a direct interaction with the target molecule DNA. Possible scenarios leading to nucleobase mispairing are discussed, and selected examples are presented. They include changes in nucleobase selectivity as a consequence of alterations in acid-base properties of nucleobase atoms and groups involved in complementary H bond formation, guanine deprotonation, and stabilization of rare nucleobase tautomers by metal ions. Oxidative nucleobase damage brought about by metal species will not be considered.

Base Pairing↗
PubMed1999

Reactivity of an extremely sterically crowded monofunctional Pt complex, [Pt(1-MeC-N3)3(H2O)]2+ (1-MeC = 1-methylcytosine), toward model nucleobases and selectivity toward guanine in single- and double-stranded deoxyoligonucleotides.

Reactions of [Pt(1-MeC-N3)3Cl]NO3 (1-MeC-N3 = 1-methylcytosine, bound to Pt via N3) and the respective aqua species [Pt(1-MeC-N3)3(H2O)]2+ with the model nucleobases 9-ethylguanine (9-EtGH), 9-methyladenine (9-MeA), single-stranded 5'd(T3GT3), and double-stranded [5'd(GA-GA2GCT2CTC)]2 have been studied in solution by means of 1H NMR spectroscopy, HPLC, and electrospray ionization mass spectrometry. Reactions are generally slow, in particular with the chloro species, and guanine is the only reactive base in the oligonucleotides. However, unlike (dien)PtII, which binds randomly to the guanines in the ds dodecamer, (1-MeC-N3)3PtII binds selectively to the terminal guanine only, probably because base fraying takes place at the duplex ends. The X-ray crystal structures of [Pt(1-MeC-N3)3(9-EtG-N7)]ClO4.8H2O (1b) and of [Pt(1-MeC-N3)3(9-MeA-N7)](ClO4)2.0.5H2O as well as NMR spectroscopic studies of [Pt(1-MeC-N3)3(9-EtGH-N7)] (NO3)2.H2O (1a) are reported. The tetrakis(nucleobase) complexes adopt a head-tail-head orientation of the three 1-MeC bases and an orientation of the fourth base (purine) that permits a maximum of intracomplex H bonds between exocyclic groups. As far as the guanine adduct (1a, 1b) is concerned, relative orientations of the four bases are identical in the model and in the oligonucleotide adduct.

DNA↗
PubMed1999

Metal ions in non-complementary DNA base pairs: an ab initio study of Cu(I), Ag(I), and Au(I) complexes with the cytosine-adenine base pair.

Ab initio calculations have been carried out to characterize the structure and energetics of a silver(I) complex with the cytosine-adenine DNA base pair and an aqua ligand in the coordination sphere of Ag. In addition, we have also studied analogous complexes with Cu(I) and Au(I), and structures in which adenine has been replaced by purine in order to investigate the structural role of the adenine amino group. The calculations revealed that all metal-modified structures are dominated by the metal-base interactions, while the water-metal ion interaction and many-body interligand repulsion are less important contributions. Nevertheless, the structural role of the water molecule in the complex is quite apparent and in agreement with an earlier crystallographic study. The metal-modified base pairs exhibit large conformational flexibility toward out-of-plane motions (propeller twist and buckle), comparable or, in some cases, even larger than that observed in the base pairs without metal ions. All structures have been optimized within the Hartree-Fock approximation, while interaction energies were evaluated with the inclusion of electron correlation.

Adenine↗
PubMed1999

trans-(NH3)(2)Pt(II)-modified deoxyoligonucleotides as potential antisense agents: cross-linking reactions between two 12-mers.

An approach is presented which probes the possible use of trans-[(NH3)(2)PtCl](+)-modified deoxyoligonucleotides in the antisense strategy. It consists of (1) the selective platination of an oligonucleotide containing 11 pyrimidine (T, C) bases as well as a single guanine (G) as a Pt-anchoring group at the 5'-end to give trans-[(NH3)(2)Pt¿5'-d(G(N7)T(2)C(2)T(2)C(2)T(2)C¿Cl](10-) 1 ("antisense strand") and (2) subsequent hybridization with the purine 12-mer 5'-d(GA(2)G(2)A(2)G(2)A(2)G)(11-) ("sense strand"). According to HPLC, three major species 2-4 are formed during reaction (2), all of which are cross-linking adducts between 1 and the sense strand, as confirmed by ESI MS and melting temperature measurements. Only for the major product 3 can a structure be proposed on the basis of 1D and 2D NMR spectra. According to these, G(1) of the antisense strand is cross-linked with G(20) via trans-(NH3)(2)Pt(II). The complementary overhangs of the duplex represent "sticky ends" and are, in principle, capable of associating into multimers of the duplex.

Cisplatin↗
PubMed1999

5,5'-Diuracilyl Species from Uracil and

Not only UV radiation can bring about the dimerization of the pyrimidine nucleobase uracil, a metal ion can as well! The reaction proceeds by a reductive elimination process of two cis-oriented uracil entities, each bonded to Au(III) through C5 [Eq. (a)]. R/R'=H/CH(3), CH(3)/CH(3), H,C(5)H(9)O(4)

Journal Article↗
PubMed1996

Interstrand cross-linking reaction in triplexes containing a monofunctional transplatin-adduct.

Our aim was to determine whether a single transplatin monofunctional adduct, either trans-[Pt(NH3)2(dC)Cl]+ or trans-[Pt(NH3)2(dG)Cl]+ within a homopyrimidine oligonucleotide, could further react and form an interstrand cross-link once the platinated oligonucleotide was bound to the complementary duplex. The single monofunctional adduct was located at either the 5' end or in the middle of the platinated oligonucleotide. In all the triplexes, specific interstrand cross-links were formed between the platinated Hoogsteen strand and the complementary purine-rich strand. No interstrand cross-links were detected between the platinated oligonucleotides and non-complementary DNA. The yield and the rate of the cross-linking reaction depend upon the nature and location of the monofunctional adducts. Half-lives of the monofunctional adducts within the triplexes were in the range 2-6 h. The potential use of the platinated oligonucleotides to modulate gene expression is discussed.

Alkylating Agents↗
PubMed1996

Trans-diammineplatinum(II): what makes it different from cis-DDP? Coordination chemistry of a neglected relative of cisplatin and its interaction with nucleic acids.

The question raised, i.e., "trans-diammineplatinum(II)--what makes it different from its cis isomer?" permits a number of answers, relating to various aspects of the chemistry of the two compounds, but the crucial one concerning antitumor activity is yet to be answered. In principle, any of the following reasons or combinations thereof might account for the observed differences in biological effects, but some are more likely than others: 1. TARGET MOLECULES: It is generally accepted that DNA is the most important target molecule of cisplatin and that inhibition of DNA synthesis correlates with antitumor activity. This fact does not contradict observations on extensive reaction with other biomolecules. The mutagenic effects of trans-a2Pt(II), although weaker than for cis-DDP, point toward DNA as being an important target for trans-DDP as well. 2. DNA ADDUCTS: As a consequence of the inherent difference in geometry, the two isomers form different adducts. Specifically, trans-DDP cannot form 1,2-intrastrand crosslinks, which represent by far the most abundant adducts of cis-DDP. On the other hand, the trans isomer displays a greater variation in nucleobase donor sites (cf. Sec. 4.2). 3. DNA STABILITY: While the 1,2-intrastrand adducts of cis-DDP, regardless if GG or AG, consistently cause DNA kinking and lead to thermal destabilization, the effects of trans-DDP adducts seem to be of a greater variability, causing thermal stabilization or destabilization. For intrastrand 1,3 adducts in puXpu sequences, the intervening base X appears to be important in this respect (cf. Sec. 4.3). 4. DNA REPAIR: In living cells, higher doses of trans-DDP as compared to cis-DDP are required to bind an equal number of Pt atoms per nucleotide [66]. On the other hand, bifunctional DNA adducts of either isomer inhibit DNA replication to the same extent [66,150,151]. This finding has been interpreted in terms of a differential repair of adducts of the two isomers [66], but an alternative explanation has also been offered [152]. It is to be noted that repair of monofunctional trans-DDP lesions does not require enzymatic repair but rather may be accomplished by any nucleophile within the cell exercising a reasonably high trans influence, e.g., an S-donor of glutathione. 5. INTRINSIC REACTIVITY: Differences in hydrolysis kinetics of the two isomers (unfavorable equilibrium concentration of trans-[(NH3)2Pt-Cl(OH2)]+ [37]) and in reaction rates of various hydrolysis species with DNA constituents [36] could, in principle, explain a difference in biological effects. On the other hand, the kinetics of reactions of the dichloro species of both isomers with DNA (in the absence of any repair agents) appear not to be that largely different to produce a strong point for differential reactivity of this species. Model studies have shown at least one more distinct difference between mono(nucleobase) adducts of both isomers: While cis-[a2PtLCl]+ can lose the amine trans to Cl, in trans-[a2PtLCl]+ Cl is capable of displaying L (cf. Sec. 6.1). Both reactions are not very fast with Cl-, but any good nucleophile replacing Cl- would do so with high efficiency. In the case of trans-DDP, such a reaction leads to removal of Pt from DNA, unlike in the case of cis-DDP (even though we are aware that cis effects may also be operative). With respect to amine displacement from monoadducts of cis-DDP, it is interesting to speculate on the fate of (toxic) NH3. Is it capable of undergoing condensation reactions with biomolecules? In theory, such a scenario might provide possibilities for the role of the amine ligands in cis-(amine)2Pt(II) compounds alternative to those commonly accepted (e.g., role of NH protons in stabilizing DNA adducts [153]). 6. TRANSPORT AND DISTRIBUTION: Despite differences in water solubility of the two isomers (trans-DDP less soluble), this property is unlikely to be important at physiological concentrations...

Antineoplastic Agents↗