Interactions of Molecules with Nucleic Acids. X. Covalent Intercalat e Binding of the Carcinogenic BPDE I(+) to Kinked DNA

Abstract

A theoretical model is proposed for the covalent binding of (+) 7 β,8α-dihydroxy-9α, 10α- epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene denoted by BPDE I(+), to N2 on guanine. The DNA must kink a minimum of 39° to allow proper hybrid configurations about the C10 and N2 atoms involved in bond formation and to allow stacking of the pyrene moiety with the non-bonded adjacent base pair. Conservative (same sugar puckers and glycosidic angles as in B-DNA) and non-conservative (alternating sugar puckers as in intercalation sites) conformations are found and they are proposed structures in pathways connecting B-DNA, an intercalation site, and a kink site in the formation of a covalently intercalative bound adduct of BPDE I(+) to N2 on guanine. Stereographic projections are presented for (3′) and (5′) binding in the DNA. Experimental data for bending of DNA by BPDE, orientation of BPDE in DNA and unwinding of superhelical DNA is explained. The structure of a covalent intercalative complex is predicted to result from the reaction. Also, an anti ? syn transition of guanine results in a structure which allows the DNA to resume its overall B-form. The only change is that guanine has been rotated by 200° about its glycosidic bond so that the BPDE I(+) is bound in the major groove. The latter step may allow the DNA to be stored with an adduct which may produce an error in the genetic code.     

Interaction of cis- and trans-RuCl2(DMSO)4 with the nucleotides GpA, d(GpA), ApG, d(ApG) and d(CCTGGTCC): high-field NMR characterization of the reaction products

 Both cis- and trans-RuCl₂(DMSO)₄ (cis-Ru and trans-Ru) react with ApG, GpA, d(ApG) and d(GpA) to yield products with bifunctional metal coordination of the bases. For each dinucleotide one major product and several minor species are formed. This is in contrast to previous results on analogous reactions between trans-Ru and d(GpG) where a substantial amount of an intermediate species was found. The rates of reaction between dinucleotides and cis-Ru are approximately 20-fold slower than for trans-Ru. The compounds formed with the two isomers exhibit identical proton NMR spectra, suggesting the same coordination mode for ruthenium in the final product. The two purine bases are coordinated to ruthenium through N7 in a head-to-head conformation with the glycosidic angles being in the anti range. Coupling constants indicate a relatively pure 3′-endo conformation for the 5′-sugar and mainly 2′-endo for the 3′-sugar. The similar bifunctional binding mode of cis- and trans-Ru(II) with dinucleotides as evident from the NMR spectra are in contrast to the different mode of interaction suggested earlier for cis- and trans-Ru complexes with DNA. trans-Ru interacts with the deoxyoctanucleotide d(CCTGGTCC), giving two main products during the first 2 h of incubation time. Four H8 guanine resonances are shifted downfield, characteristic of N7 metal coordination. The products are not analyzed in detail, but it is suggested that the structures may be described as two chiral G(N7/N7) chelates. Received: 20 August 1998 / Accepted: 20 January 1999     

Modeling DNA Hydration: Comparison of Calculated and Experimental Hydration Properties of Nuclic Acid Bases

Abstract

Hydration properties of individual nucleic acid bases were calculated and compared with the available experimental data. Three sets of classical potential functions (PF) used in simulations of nucleic acid hydration were juxtaposed: (i) the PF developed by Poltev and Malenkov (PM), (ii) the PF of Weiner and Kollman (WK), which together with Jorgensen's TIP3P water model are widely used in the AMBER program, and (HI) OPLS (optimized potentials for liquid simulations) developed by Jorgensen (J). The global minima of interaction energy of single water molecules with all the natural nucleic acid bases correspond to the formation of two water-base hydrogen bonds (water bridging of two hydrophilic atoms of the base). The energy values of these minima calculated via PM potentials are in somewhat better conformity with mass-spectrometric data than the values calculated via WK PF. OPLS gave much weaker water-base interactions for all compounds considered, thus these PF were not used in further computations. Monte Carlo simulations of the hydration of 9- methyladenine, 1-methyluracil and 1-methylthymine were performed in systems with 400 water molecules and periodic boundary conditions. Results of simulations with PM potentials give better agreement with experimental data on hydration energies than WK PF. Computations with PM PF of the hydration energy of keto and enol tautomers of 9-methyl- guanine can account for the shift in the tautomeric equilibrium of guanine in aqueous media to a dominance of the keto form in spite of nearly equal intrinsic stability of keto and enol tautomers. The results of guanine hydration computations are discussed in relation to mechanisms of base mispairing errors in nucleic acid biosynthesis. The data presented in this paper along with previous results on simulation of hydration shell structures in DNA duplex grooves provide ample evidence for the advantages of PM PF in studies of nucleic-acid hydration.     

Elbow Flexibility of the kt38 RNA Kink-Turn Motif Investigated by Free-Energy Molecular Dynamics Simulations

Kink-turns (K-turns) are common structural motifs that can introduce sharp kinks into double-stranded RNA, and have been proposed to mediate large-scale motions in the ribosome. K-turns consist of a bulge loop region flanked by trans sugar-Hoogsteen G:A pairs, and the sharp kink conformation is stabilized by A-minor interactions (adenine contacting a G:C basepair in the minor groove). Umbrella-sampling molecular dynamics simulations were used to disrupt an A-minor interaction in the ribosomal kt38 turn and to calculate the associated free-energy change. Coupling of umbrella sampling with replica exchanges between neighboring umbrella-sampling intervals could further improve the convergence of the free-energy calculations. The simulations revealed a coupled A-minor disruption and global opening of the K-turn motif, and allowed us to characterize several intermediate A-minor conformations. The calculated free-energy profile indicated a meta-stable, semi-open structure of slightly higher free energy (∼1 kcal mol⁻¹), separated by a small free-energy barrier (∼1.5 kcal mol⁻¹) from the closed (highly kinked) form. Both K-turn states are stabilized by distinct variants of the A-minor interaction. Further opening of the K-turn structure required significantly larger free-energy changes. The semi-open form had a reduced kink angle compatible with experimental data on K-turn solution structures, and opening was coupled to a continuous global unwinding of the K-turn motif. The range of free-energy changes associated with kt38 opening and unwinding are compatible with the idea that K-turns may facilitate biologically relevant motions during large-scale ribosome dynamics.     

Design and SAR Study of a Novel Class of Nucleotide Analogues as Potent Anti-HCMV Agents

Abstract

We have developed a novel class of 2-phosphonate 1,3-dioxolane nucleotide analogues, from which the guanine derivative displayed weak anti-HCMV activity. Further SAR studies led to the identification of both cis and trans guanine derivatives of tetrahydrofuran analogues as potent anti-HCMV agents, both in vitro and in vivo, compared to ganciclovir and HPMPC.     

DFT study of new bipyrazole derivatives and their potential activity as corrosion inhibitors

In the present work, a theoretical study of five bipyrazolic-type organic compounds, 4-{bis[(3,5-dimethyl-1H-pyrazolyl-1-yl)methyl]-amino}phenol (1), N1,N1-bis[(3,5-dimethyl-1H-pyrazol-1-yl)methyl}]-N4,N4-dimethyl-1,4-benzenediamine (2), N,N-bis[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]aniline (3), 4-[bis(3,5-dimethyl pyrazol-1-yl-methyl)-amino]butan-1-ol (4) and ethyl4-[bis(3,5-dimethyl-1H-pyrazol-1-yl-methyl) aminobenzoate] (5), has been performed using density functional theory (DFT) at the B3LYP/6-31G(d) level in order to elucidate the different inhibition efficiencies and reactive sites of these compounds as corrosion inhibitors. The efficiencies of corrosion inhibitors and the global chemical reactivity relate to some parameters, such as EHOMO, ELUMO, gap energy (ΔE) and other parameters, including electronegativity (χ), global hardness (η) and the fraction of electrons transferred from the inhibitor molecule to the metallic atom (ΔN). The calculated results are in agreement with the experimental data on the whole. In addition, the local reactivity has been analyzed through the Fukui function and condensed softness indices.     

Biophysical characterization and molecular modeling of the coordinative-intercalative DNA monoadduct of a platinum-acridinylthiourea agent in a site-specifically modified dodecamer

The guanine-N7 monoadduct of [Pt(en)Cl(ACRAMTU)](NO₃)₂ (PT-ACRAMTU; en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea), a dual metalating/intercalating cytotoxic agent, was generated in a double-stranded dodecamer, d(CCTCTCG*TCTCC/GGAGACGAGAGG) (III*), and isolated by preparative reverse-phase high-performance liquid chromatography (HPLC). The adduct was characterized using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), circular-dichroism spectropolarimetry (CD), UV-melting curves, and NMR spectroscopy. In addition, a molecular mechanics/restrained molecular dynamics (MM/rMD) study was performed for this adduct using the AMBER force field. Monoadduction of the sequence leads to a pronounced increase in melting temperature, T_m=T_m(III*)–T_m(III)=9.7 °C. Because there is complete enthalpy–entropy compensation, binding occurs without noticeable thermodynamic destabilization. This feature and the CD (induced-ligand circular dichroism) and NMR (upfield shifts of aromatic acridine proton signals) data are indicative of a unique, nondenaturing dual-binding mode that involves partial intercalation of the acridine chromophore. An energy-minimized AMBER model of III* demonstrates that platination of G7-N7 of guanine in the major groove and partial insertion of the acridine moiety into the C6G19/G7C18 base step on the 5 face of the modified purine base is feasible and supportive of the experimental results. Differences in the biophysical properties between III* and duplexes containing adducts of the clinical-drug cisplatin are outlined, and possible biological consequences are discussed.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00775-004-0534-3Abbreviations ACRAMTU 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea - dGuo 2-deoxyguanosine - dGuo* [Pt(en)(ACRAMTU-S)(dGuo-N7)]³⁺ - en ethane-1,2-diamine - ICD Induced circular dichroism - MALDI-TOF MS Matrix-assisted laser desorption ionization time-of-flight mass spectrometry - MM Molecular mechanics - PIPES 1,4-piperazinediethanesulfonic acid - PT-ACRAMTU [Pt(en)Cl(ACRAMTU)](NO₃)₂ - rMD Restrained molecular dynamics     

领春木枝叶化学成分的研究

为了研究领春木(Euptelea pleiospermum Hook.f.et Thoms)的化学成分,利用各种柱色谱及高压液相色谱等方法进行分离和纯化,根据理化性质和光谱数据分析鉴定了9个化合物。他们分别为:白桦脂酸(1);齐墩果酸(2);N-反式对羟基肉桂酰基-对羟基苯乙胺(3);N-反式阿魏酰酪胺(4);N-顺式阿魏酰酪胺(5);丁香脂素(6);N-顺式阿魏酰-3-甲氧基酪胺(7);N-反式阿魏酰-3-甲氧基酪胺(8);3-羟基-30-去甲基-20-酮基-28-羽扇豆酸(9)。所有化合物均为首次从领春木中分离得到。     

‘Chargaff's Rules’ for Protein Folding: Stoichiometric Leitmotif Made Visible

Abstract

The complex between cobalt hexammine and decadeoxyoligomer d(CGTACGTACG) crystallizes into the space group P6₅ with unit cell constants a = b = 17.93Å, and c = 43.41Å. The molecules have the helix axis coincident with the crystal c-axis. The decamers stack on top of each other and form a quasi-continuous helix. The structure is disordered. The asymmetric unit is a dimer (pPyr-pPur)₂ with each base pair 60% of the time a C-G and 40% of the time a T-A. Restrainted least-squares refinement led to an R-factor of 25.5% for 506 observed reflections above the two-sigma level. The structure was found to have one strand in the Z_I-conformation and the other in the Z_II-conformation. The cobalt hexammine binds to two Z_II-chains of symmetrically related molecules. On one Z_II chain, two ammonia molecules of the cobalt hexammine bind to the N7 nitrogen and 06 oxygen atoms of the guanine bases and a third ammonia to the phosphate anionic oxygen atom of the preceding pyrimidine base, resulting in an “external” binding mode. On the other Z_II chain, one ammonia molecule of the cobalt hexammine binds only to the anionic oxygens of the phosphate group of the guanine bases, leading to an “internal” binding mode. Thus, the basis of the stabilization of Z-DNA by [Co(NH₃)₆]³⁺ is its binding to only guanine nucleotides. It is surmised that statistical disordering of deoxyoligonucleotide structures which take a Z conformation, depends on the length of the oligomer. That is to say, octamers and decamers (which cannot use an integral number of molecules for a 12 base pair repeat) form disordered structures whereas tetramers and hexamers form well ordered structures.     

Parallel-Stranded DNA with Natural Base Sequences

Noncanonical parallel-stranded DNA double helices (ps-DNA) of natural nucleotide sequences are usually less stable than the canonical antiparallel-stranded DNA structures, which ensures reliable cell functioning. However, recent data indicate a possible role of ps-DNA in DNA loops or in regions of trinucleotide repeats connected with neurodegenerative diseases. The review surveys recent studies on the effect of nucleotide sequence on preference of one or other type of DNA duplex. (1) Ps-DNA of mixed AT/GC composition was found to have conformational and thermodynamic properties drastically different from those of a Watson–Crick double helix. Its stability depends strongly on the specific sequence in a manner peculiar to the ps double helix, because of the energy disadvantage of the AT/GC contacts. The AT/GC boundary facilitated flipping of A and T out of the ps double helix. Proton acceptor groups of bases are exposed into both grooves of the ps-DNA and are accessible to solvent and ligands, including proteins. (2) DNA regions containing natural minor bases isoguanine and isomethylisocytosine were shown to form ps-DNA with transAT-, trans isoGC, and transiso^5meCG pairs exceeding in stability a related canonical duplex. (3) Nucleotide sequence dG(GT)₄G from yeast telomeres and microsatellites was demonstrated to form novel ps-DNA with GG and TT base pairing. Unlike d(GT) _n - and d(G _n T _m ) sequences able to form quadruplexes, the dG(GT)₄G sequence formed no alternative double- or multistranded structures in a wide range of experimental conditions, thus suggesting that the nucleotide context governs the observed structural polymorphism of the d(GT) _n sequence. The possible biological role of ps-DNA and the prospects of its study are discussed.     

Electronic structure of platinum(II) antitumor complexes and their interactions with nucleic acid bases. I

Using the semi-empirical all-valence method (GRINDOL) (recently modified and extended to transition series elements), electronic structure and intermolecular interactions of the model antitumor Pt(II) compounds with guanine and thioguanine have been calculated. Several possible models of antitumor action of platinum compounds are discussed. It is concluded that cis-Pt(II) complexes with guanine form stable intrastrand N7N7 cross-links (but chelation to the O6 atom is also possible). The trans-isomers of platinum(II) exclusively form interstrand cross-links, but the cis-Pt(II) complexes with thioguanine form almost entirely the N7S five-membered chelates.     

Dynamic studies of the unwinding of a DNA-like strand

Following Simon and Zimm's recent work, both molecular dynamic and Monte Carlo methods are used to simulate on a computer the unwinding of a DNA-like (N + 1)-unit helical strand. The strand unwinding is assumed to obey (N + 1)-coupled Langevin equations of motion (N = 10–50). The present computer “experiment” was done to elaborate dependence of unwinding behavior of the helix upon (i) configurations of its complementary strand [represented here by a square cylinder (Simon-Zimm model), a circular cylinder, and a fixed helix (double-helical model)]; (ii) interstrand potentials (a hard-cylinder potential, an inverse twelfth-power soft repulsion with or without an inverse third-power attractive tail); (iii) amplitudes of the Brownian motions, and (iv) the molecular weights of the unwinding strand. We found that (i) the Brownian motions strongly couple with the interstrand potentials to produce a shorter “unwinding time” (τ₀) (which characterizes an expotential decay of the unwinding) for a longer renged repulsive potential (without the Brownian motions, no such effect was present); (ii) addition of an attractive tail to the repulsive potentials further reinforces the unwinding, thereby giving a reduced value of τ₀; (iii) τ₀ can be expressed as a product of two factors–unwinding time for a one-dimensional spring-bead model, which mostly accounts for the N ²-dependence in τ₀, and a factor which depends on the Brownian motions and the interstrand potentials; (iv) among the three models described above, under similar situations, the three-dimensional double-helical model has the smallest τ₀; and (v) unless the maximum Brownian displacement exceeds a certain value, the unwinding around a square cylinder takes place in a (unrealistic) stair-step manner whose τ₀ decreases with increase in the Brownian displacements. The N ²-dependence of τ₀ agrees with the Simon and Zimm's machine results as well as Crother's experimental data on T2 DNA; however, it contradicts experimental data of Massie and Zimm, and others. Further possible improvements in connection with the computer simulation are suggested.     

Microbial Allyl Rearrangement and Resolution of Acetates of Unsaturated Cyclic Terpene Alchols by Pseudomonas sp. NOF-5 Strain

Microbial hydrolysis of the acetates of unsaturated cyclic terpene alcohols by Pseudomonas sp. NOF-5 isolated from soil was investigated. (±)-trans-Carveyl acetate ((±)-trans-3) was enantio-selectively hydrolyzed with NOF-5 strain to give ( – )-trans-carveol (( – )-trans-2 of 86.6% optical purity). However, the hydrolysis of (±)-cis-3 was less enantioselective, while (±)-piperitylacetate ((±)-6, a cis and trans mixture) was hydrolyzed to give the ( – )-trans- and ( – )-cis-piperitols (( – )- trans-5 and ( – )-cis-5) in a poor optical yield. In this case, other tert-alcohols, ( + )-trans- and ( – )- ds-2-p-menthen-1-ols ((±)-trans-7 and ( – )-cis-7), were also produced. Furthermore, microbial and enzymic allyl rearrangements of ( + )-trans-6 and ( – )-trans-verbenylacetate (( – )-trans-11) were studied. Biological treatment of (+)-trans-6 and ( – )-trans-11 with NOF-5 or its esterase gave (+)-trans- and (-)-cis-1 and ( + )-cis-3-pinen-2-ol (( + )-cis-12), respectively.     

Conformational Changes Induced in the Human Protein Translin and in the Single-stranded Oligodeoxynucleotides d(GT)12 and d(TTAGGG)5 Upon Binding of These Oligodeoxynucleotides by Translin

Abstract

Translin is a human single-stranded DNA and RNA binding protein that has been highly conserved in eukaryotic evolution. It consists of eight subunits having a highly helical secondary structure that assemble into a ring. The DNA and the RNA are bound inside the ring. Recently, some of us demonstrated that the human translin specifically binds the single-stranded microsatellite repeats, d(GT)_n, the human telomeric repeats, d(TTAGGG)_n, and the Tetrahymena telomeric repeats, d(GGGGTT)_n. These data suggested that translin might be involved in recombination at d(GT)_n·d(AC)_n microsatellites and in telomere metabolism [E. Jacob, L. Pucshansky, E. Zeruya, N. Baran, H. Manor. J. Mol. Biol. 344, 939–950 (2004), S. Cohen, E. Jacob, H. Manor. Biochim. Biophys. Acta. 1679, 129–140 (2004)]. Other data indicated that translin might stimulate binding of telomerase to single- stranded telomeric overhangs by unwinding secondary structures formed by the telomeric repeats [S. Cohen, E. Jacob, H. Manor. Biochim. Biophys. Acta. 1679, 129–140 (2004)]. Here we present a circular dichroism (CD) analysis of complexes formed between the human translin and the microsatellite and telomeric oligodeoxynucleotides d(GT) and d(TTAGGG)5. We report that conformational changes occur in both the translin and the oligodeoxynucleotides upon formation of the complexes. In translin octamers bound to the oligodeoxynucleotide d(GT)12, the fraction of a-helices decreases from ～67% to ～50%, while the fraction of turns and of the unordered structure increases from ～11% to ～17% and from ～19% to ～24%, respectively. In the bound oligodeoxynucleotide d(GT), we observed CD shifts which are consistent with a decrease of base stacking and a putative anti-syn switch of some guanines. The oligodeoxynucleotide d(TTAGGG)5 formed intramolecular quadruplexes under the conditions of our assays and translin was found to unfold the quadruplexes into structures consisting of a single hairpin and three unwound single-stranded d(TTAGGG) repeats. We suggest that such unfolding could account for the stimulation of telomerase activity by translin mentioned above.     

Enzyme mediated resolution of alcohols

Summary The racemic cis and trans isomers 1a and 1b of 2-(4-methoxybenzyl)-1-cyclohexanol were subjects of an enzyme mediated resolution via esterification in organic solvents, in which the chiral esters 2a and 2b of the corresponding alcohols 4a and 4b, and the chiral alcohols 3a and 3b were obtained. The chemical yield and enantioselectivity of this enzymatic reaction have been found to depend mainly on (a) the structure of the substrate (cis or trans), (b) temperature, (c) the nature of the enzyme selected, and (d) the nature of the solvent.     

喙果皂帽花根的化学成分研究

为了解喙果皂帽花(Dasymaschalon rostratum)根的化学成分,采用多种色谱技术从其根的乙醇提取物中分离得到8个化合物。通过波谱数据分析,分别鉴定为:花旗松素(1)、(+)-儿茶素(2)、毛蕊异黄酮(3)、(-)-丁香树脂酚(4)、(-)-皮树脂醇(5)、lirioresinol A(6)、N-反式肉桂酸酰对羟基苯乙胺(7)和羟基酪醇(8)。所有化合物均为首次从该植物中获得。化合物1~8均无明显抗菌活性。     

Free Radical-Induced Tandem Base Damage in DNA Oligomers

A new tandem base lesion has been identified in two DNA oligomers, namely d(GpT) and d(CpGpTpA), exposed to X-irradiation in deoxygenated aqueous solution. In this lesion the C6 carbon atom of thymine is hydroxylated and a covalent link is formed between the C5 carbon atom of thymine and the C8 carbon atom of the adjacent guanine base. In addition, further evidence in the form of mass spectrometric data is presented confirming the structures of previously reported tandem base lesions that are produced by ionizing radiation in the presence of oxygen. New data is presented on the prevalence of a previously reported tandem base lesion in which the methyl carbon atom of thymine is covalently linked to the C8 carbon atom of the adjacent guanine base. The free radical-initiated processes by which tandem base damages are generated are discussed. To date four different radiation-induced tandem base lesion have been identified. The evidence suggests that tandem base damage is a significant component of free radical-induced DNA damage.     

trans-(NH3)2PtII-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)₂PtCl]⁺-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)₂Pt{5′-d(G^N7T₂C₂T₂C₂T₂C}Cl]^10– 1 ("antisense strand") and (2) subsequent hybridization with the purine 12-mer 5′-d(GA₂G₂A₂G₂A₂G)^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, G₁ of the antisense strand is cross-linked with G₂₀ via trans-(NH₃)₂Pt^II. The complementary overhangs of the duplex represent "sticky ends" and are, in principle, capable of associating into multimers of the duplex. Received: 29 March 1999 / Accepted: 26 July 1999     

Steric control of DNA interstrand cross-link sites of <Emphasis Type="Italic">trans</Emphasis> platinum complexes: specificity can be dictated by planar nonleaving groups

trans -dichloroplatinum(II) complexes exhibit antitumor activity violate the classical structure-activity relationships of platinum(II) complexes. These novel “nonclassical”trans platinum complexes also comprise those containing planar aromatic amines. Initial studies have shown that these compounds form a considerable amount of DNA interstrand cross-links (up to ∼30%) with a rate markedly higher than clinically ineffective transplatin. The present work has shown, using Maxam-Gilbert footprinting, that trans-[PtCl₂(NH₃)(quinoline)] and trans-[PtCl₂(NH₃)(thiazole)], representatives of the group of new antitumor trans-dichloroplatinum complexes containing planar amines, preferentially form DNA interstrand cross-links between guanine residues at the 5′-GC-3′ sites. Thus, DNA interstrand cross-linking by trans-[PtCl₂(NH₃)(quinoline)] and trans-[PtCl₂(NH₃)(thiazole)] is formally equivalent to that by antitumor cisplatin, but different from clinically ineffective transplatin which preferentially forms these adducts between complementary guanine and cytosine residues. This result shows for the first time that simple chemical modification of the structure of an inactive compound alters its DNA binding site into a DNA adduct of an active drug. Received: 6 January 2000 / Accepted: 8 March 2000     

Minor-Groove Binding Models for Acetylaminofluorene Modified DNA

Abstract

Minimized potential energy calculations have been employed to locate and evaluate energetically a number of different models for DNA modified at carbon-8 of guanine by acetylaminofluorene (AAF). Three different duplex nonamer sequences were investigated. In addition to syn guanine models which have some denaturation and a Z-DNA model, we have found two new types of structures in which guanine remains syn and the AAF is placed in the minor groove of a B-DNA helix. One type features Hoogsteen base pairing between the modified guanine and protonated cytosine, with a sharply bent helix. The other (here termed the “wedge” model because the aromatic amine is wedged into the minor groove) maintains a single hydrogen bond between O6 of the modified guanine and N3 of protonated cytosine, with much less deformation of the helix, and close Van der Waals contacts between the AAF and the walls of the minor groove. Both types of structures (as well as the related forms produced by deprotonation of cytosine) are energetically important in all three sequences examined. The wedge-type model, which is most favored except in alternating G-C sequences, has been previously observed in a combined NMR and computational characterization of an aminofluorene (AF) modified guanine opposite adenine in a DNA duplex undecamer (D. Norman, P. Abuaf, B.E. Hingerty, D. Live, D. Grunberger, S. Broyde and D.J. Patel, Biochemistry 28, 7462 (1989)).