Modeling the action of an antitumor drug: a density functional theory study of the mechanism of tirapazamine

Density functional theory methods are employed to investigate experimentally proposed mechanisms by which the antitumor drug tirapazamine may react with a DNA sugar-C(1)' radical to give the sugar derivative deoxyribonolactone, with concomitant DNA strand breakage. For the previously proposed minor pathway, ionization of the sugar-C(1)' radical by tirapazamine, the calculated ionization energy, and the electron affinity of the models of the sugar-C(1)' radical of DNA and tirapazamine suggest that tirapazamine must be protonated to be able to oxidize the sugar-C(1)' radical. The preferred mechanism for reaction of tirapazamine with a sugar-C(1)' radical, in agreement with experimental observations, is found to proceed by direct attack of an N-oxide oxygen of tirapazamine at the sugar-C(1)' position, followed by homolytic cleavage of the N-O bond of the drug moiety. Possible alternative mechanisms are also investigated.     

Validated method for the determination of the novel organo-ruthenium anticancer drug NAMI-A in human biological fluids by Zeeman atomic absorption spectrometry

NAMI-A is a novel ruthenium-containing experimental anticancer agent. We have developed and validated a rapid and sensitive analytical method to determine NAMI-A in human plasma, plasma ultrafiltrate and urine using atomic absorption spectrometry with Zeeman correction. The sample pretreatment procedure is straightforward, involving only dilution with an appropriate hydrochloric acid buffer-solution. Because the response signal of the spectrometer depended on the composition of the sample matrix, in particular on the amount of human plasma in the sample, all unknown samples were diluted to match the matrix composition in which the standard line was prepared (plasma-buffer 1 : 10 v/v). This procedure enabled the measurement of samples of different biological matrices in a single run. The validated range of determination was 1.1–220 μM NAMI-A for plasma and urine, and 0.22–44 μM for plasma ultrafiltrate. The lower limit of detection was 0.85 μM in plasma and urine and 0.17 μM in plasma ultrafiltrate. The lower limit of quantitation was 1.1 and 0.22 μM, respectively. The performance of the method, in terms of precision and accuracy, was according to the generally accepted criteria for validation of analytical methodologies. The applicability of the method was demonstrated in a patient who was treated in a pharmacokinetic phase I trial with intravenous NAMI-A. Received: 1 September 2000 / Revised: 1 November 2000 / Accepted: 12 November 2000     

Validated method for the determination of the novel organo-ruthenium anticancer drug NAMI-A in human biological fluids by Zeeman atomic absorption spectrometry

NAMI-A is a novel ruthenium-containing experimental anticancer agent. We have developed and validated a rapid and sensitive analytical method to determine NAMI-A in human plasma, plasma ultrafiltrate and urine using atomic absorption spectrometry with Zeeman correction. The sample pretreatment procedure is straightforward, involving only dilution with an appropriate hydrochloric acid buffer-solution. Because the response signal of the spectrometer depended on the composition of the sample matrix, in particular on the amount of human plasma in the sample, all unknown samples were diluted to match the matrix composition in which the standard line was prepared (plasma-buffer 1:10 v/v). This procedure enabled the measurement of samples of different biological matrices in a single run. The validated range of determination was 1.1-220 microM NAMI-A for plasma and urine, and 0.22-44 microM for plasma ultrafiltrate. The lower limit of detection was 0.85 microM in plasma and urine and 0.17 microM in plasma ultrafiltrate. The lower limit of quantitation was 1.1 and 0.22 microM, respectively. The performance of the method, in terms of precision and accuracy was according to the generally accepted criteria for validation of analytical methodologies. The applicability of the method was demonstrated in a patient who was treated in a pharmacokinetic phase I trial with intravenous NAMI-A.     

An electroanalytical study of the anticancer drug dacarbazine

The electrochemical behaviour of dacarbazine [5-(3,3-dimethyl-1-triazenyl) imidazole-4-carboxamide; DTIC] was investigated by Tast and differential pulse polarography (d.p.p.) at the dropping mercury electrode, by cyclic and differential pulse voltammetry at the hanging mercury drop electrode and by anodic voltammetry at the glassy carbon electrode. Calibration graphs were obtained for 2×10^?8?2×10^?5 M DTIC by d.p.p., for 5×10^?9?1×10^?5 M by adsorptive stripping voltammetry ar a hanging mercury drop electrode, and for 1?10×10^?5 M by high-performance liquid chromatography with oxidative amperometric detection at a glassy carbon electrode. The methods are compared and applied to determine DTIC added to blood serum after a simple clean-up procedure.     

Novel platinum‐based anticancer drug: a complete vibrational study

The introduction of cisplatin to oncology, in the 1970s, marked the onset of the search for novel and improved metal‐based anticancer drugs. Polynuclear Pt^II and Pd^II complexes with linear alkylamines as bridging ligands are a class of potential antineoplastic agents that have shown promising cytotoxicity against low‐prognosis human cancers, such as metastatic breast adenocarcinoma and osteosarcoma. The present study reports an analysis of [μ‐N,N′‐bis(3‐aminopropyl)butane‐1,4‐diamine‐κ⁴N,N′:N′′,N′′′]bis[dichloridoplatinum(II)], [Pt₂Cl₄(C₁₀H₂₆N₄)], denoted Pt₂Spm (Spm is spermine), by vibrational spectroscopy coupled to theoretical calculations. Within the latter, the Density Functional Theory (DFT – mPW1PW/6‐31G*) and Effective Core Potential (ECP – LANL2DZ) approaches were used, in order to ensure the most accurate representation of the molecule and achieve a maximum agreement with the experimental data. The solid‐state geometry of Pt₂Spm corresponds to C_i symmetry, displaying 132 vibrational modes. A complete assignment of the experimental vibrational profile of the system was attained through the combined application of complementary Raman, FT–IR and Inelastic Neutron Scattering (INS) techniques. INS allowed an unequivocal identification of the CH₂ and NH₂ rocking modes, not clearly detected by the optical techniques, while Raman measurements led to a clear discrimination of the Pt—N stretching frequencies from the two distinct Pt—N moieties within the chelate. The metal‐to‐metal distances calculated for the molecule under study were found to allow the establishment of effective inter‐ and intrastrand crosslinks with DNA. These results will hopefully help to clarify the mode of action of the compound, at the molecular level, contributing to the development of improved cisplatin‐like chemotherapeutic drugs having a higher efficacy and specificity coupled to lower acquired resistance and deleterious side effects.     

Isomerization and decomposition of germiranes: a density functional study

The formation and decomposition pathways of germiranes (germacyclopropanes), i.e., products of reactions of the GeH₂ and GeMe₂ germylenes with ethylene, tetramethylethylene, buta-1,2,3-triene, and tetramethylbuta-1,2,3-triene, were studied using the density functional approach (PBE/TZ2P approximation). The thermodynamic stabilities of the structures under consideration were evaluated by calculating the Gibbs free energies under normal conditions (ΔG°₂₉₈). Addition of germylenes to the C=C bond can proceed as a single-step process without a barrier or involve the formation of a π-complex (the barrier to this process is lower than the sum of the energies of isolated reactants). Stability of the germiranes formed is determined by their stability to retrodecomposition into the initial germylene and olefin and to the three-membered ring opening followed by simultaneous 1,2-migration of the substituent at the Ge atom and formation of the secondary germylene. Alkyl substituents can efficiently block the opening of the three-membered ring and transformation of the cyclic structure into the secondary germylene, simultaneously decreasing the germirane stability to retrodecomposition. Decomposition into germylene and olefin under normal conditions is thermally favorable for hexamethylgermirane (ΔG°₂₉₈ = −5.7 kcal mol⁻¹), being thermally forbidden for the other germiranes studied in this work (Δ G°₂₉₈ > 0). The activation energy (E _a) for the germirane ring opening depends on the substituents at the germanium atom, namely, E _a ≤ 10 kcal mol⁻¹ for unsubstituted germiranes and E _a > 30 kcal mol⁻¹ for methyl-substituted germiranes. Taking the experimentally isolated germirane as an example, it was shown how the introduction of substituents and modification of the carbon skeleton make it possible to stabilize the germacyclopropane system. Dedicated to Academician A. L. Buchachenko on the occasion of his 70th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1943–1951, September, 2005.     

Mechanisms of difluoroethylene ozonolysis: a density functional theory study

We present a density functional theory (DFT) study on the mechanisms of gas-phase ozonolysis of three isomers of difluoroethylene, namely, cis-1,2-difluoroethylene, trans-1,2-difluoroethylene, and 1,1-difluoroethylene. MPW1K/cc-pVDZ and BHandHLYP/cc-pVDZ methods are employed to optimize the geometries of stationary points as well as the points on the minimum energy path (MEP). The energies of all the points were further refined at the QCISD(T)/cc-pVDZ and QCISD(T)/6-31+G(df,p) levels of theory with zero-point energy (ZPE) corrections. The ozone-cis-1,2-difluoroethylene reaction is predicted to be slower than the ozone-trans-1,2-difluoroethylene reaction. The enhanced reactivity of trans-1,2-difluoroethylene relative to the cis isomer is similar to the reactions of ozone with cis- and trans-dichloroethylene. The ozone-1,1-difluoroethylene reaction is predicted to be slower than the ozone-trans-1,2-difluoroethylene reaction. These results are in agreement with experimental studies. The calculated mechanisms indicate that in ozone-difluoroethylene reactions the yields of OH might be trivial, which is different from the reactions of ozone with unsaturated hydrocarbons.     

Coordination-driven self-assembly of ruthenium-based molecular-rectangles: synthesis, characterization, photo-physical and anticancer potency studies

A suite of eight cationic, tetra-metallic molecular rectangles (1-8) was generated via coordination-driven self-assembly using four dicarboxylate-bridged arene-Ru precursors (A1-A4) with one of two dipyridyl ligands (D1, D2). The high-yielding (84-92%) rectangles were characterized by (1)H NMR and HR-ESI-MS to support their structural assignments. The molecular structure of 5 was determined by single crystal X-ray analysis, which indicated that two D2 ligands bridge two A1 acceptors to form a rectangular construct. The photophysical properties of these metalla-rectangles and their molecular precursors were also investigated, as well as an MTT assay to evaluate the in vitro cytotoxicities relative to two chemotherapeutic agents, cisplatin and doxorubicin. MTT assays were conducted using SK-hep-1 (liver cancer) and HCT-15 (colon cancer) human cancer cell lines. Compounds 3, 4, 7 and 8 showed significant activity, with IC(50) values comparable to those of cisplatin and doxorubicin.     

Bubble nucleation in micellar solution: a density functional study

We explore the free energetics of bubble nucleation in the micellar solution subjected to a negative pressure using a density functional model of a non-ionic surfactant solution. In this two-component model, the solvent is represented by a single hard-core sphere and the surfactant is represented by two tangent hard-core spheres connected by a rigid bond. The attractive interactions between the particles are modeled by the simple 1/R(6) form. Under all conditions of pressure and interparticle interactions we studied, the free energy barrier of bubble nucleation is found to be lower in the binary surfactant solution than that in a pure solvent and to continue to decrease as the mole fraction of the surfactant in the solution increases. We analyze the free energy surface of the model system under the conditions where both the critical bubble nucleus and the stable micelle exist in equilibrium with the same metastable solution. Our study shows that at moderately low pressures, bubbles can nucleate from the stable micelle and that the resulting free energy barrier of bubble nucleation is expected to be lower than that in the absence of this mechanism. However, as the spinodal is approached at lower pressures, the mechanism of micelle-assisted bubble nucleation becomes less effective. The liquid-liquid miscibility of the model system correlates well with the mechanism of bubble nucleation from the stable micelle.     

Substituent effects on benzdiyne: a density functional theory study

Density functional theory (DFT) studies were performed to investigate the effect of substituents on the properties of benzdiyne derivatives. Twelve substituted benzdiynes-C(6)X(2), where X = F, Cl, Br, Me, CF(3), CN, OH, NO(2), NH(2), OMe, NMe(2), and Ph-were considered along with the unsubstituted 1,4-benzdiyne. The structures, vibrational frequencies, and IR intensities of these benzdiynes were studied with a popular three-parameter hybrid density functional (B3LYP) combined with the split-valence 6-31G(d) basis set and Dunning's correlation-consistent polarized triple-zeta (cc-pVTZ) basis set. The relative stabilities of the substituted benzdiynes were studied with the help of reaction energies of isodesmic reactions, which showed that the electron-withdrawing groups destabilized the benzdiynes more than they did the corresponding benzenes, whereas the electron-donating groups stabilized the benzdiynes more than they did their benzene counterparts. Correlation analyses revealed that field/inductive effects played a more important role than did resonance effects. The changes in atomic charges and spin populations due to the substituents were also studied. The asymmetric nu(Ctbd1;C) stretching modes obtained were close to the 1500-cm(-)(1) mark. Reinvestigation of the experimental results supported these results; a weak IR band at 1486 cm(-)(1) was assigned to this asymmetric stretching mode in C(6)(CF(3))(2) F. Some other benzdiynes also had large IR intensity values for their asymmetric nu(Ctbd1;C) vibrational modes due to the coupling with other vibrational modes. Heats of formation for the substituted benzdiynes were obtained from the reaction energies calculated at the B3LYP/cc-pVTZ level of theory.     

High-pressure transitions in bulk mercury: a density functional study

We provide a consistent treatment of the known solid-state phases of mercury to high pressure to determine the phase changes at 0 K by using the local density approximation (LDA). We obtain good agreement with experimental measurements demonstrating that LDA performs well in the repulsive region of the inter-atomic interaction. The known ??-, ??-, ??-, and ??-phases of mercury differ energetically by no more than 0.04?eV and therefore provide a challenge to future high accuracy calculations using either wavefunction or density functional-based approximations.     

Laser ionization of solid RDX: a density functional theory study

Structural Chemistry - Structural changes induced via ionization in an RDX lattice have been studied by using optimized [(RDX)2]0 conformers comprising eight combinations of four RDX isomers using...     

NLO properties of metallabenzene-based chromophores: a time-dependent density functional study

The static and dynamic first hyperpolarizabilities for a series of substituted metallabenzene-based nonlinear optical (NLO) chromophores were determined by time-dependent density functional theory (TDDFT). The electronic excitation contributions to the first hyperpolarizability are rationalized in terms of the two-level model. The effects on the hyperpolarizabilities of (a) the metal center (Os, Ir, Pt); (b) the ligand environment (PH3, CO, Cl); (c) various donor and acceptor substituents (NH2, OH, Me, H, Cl, Br, I, COOMe, COOH, CN, NO2); and (d) the length of pi-conjugation were studied. Our calculations predict that metallabenzenes have significant second-order NLO susceptibilities, ranging from = 1.0 x 10(-29) to 5.6 x 10(-28) esu and from mu = 3.0 x 10(-47) to 1.1 x 10(-44) esu, that can be tuned by changing the metal center and/or ligand environment.     

Atmospheric oxidation mechanism of p-xylene: a density functional theory study

We report an investigation of the mechanistic features of OH-initiated oxidation reactions of p-xylene using density function theory (DFT). Reaction energies for the formation of the aromatic intermediate radicals have been obtained to determine their relative stability and reversibility, and their activation barriers have been analyzed to assess the energetically favorable pathways to propagate the p-xylene oxidation. OH addition is predicted to occur dominantly at the ortho position, with branching ratios of 0.8 and 0.2 for ortho and ipso additions, respectively, and the calculated overall rate constant is in agreement with available experimental studies. Under atmospheric conditions, the p-xylene peroxy radicals arising from initial OH and subsequent O(2) additions to the ring are shown to cyclize to form bicyclic radicals, rather than to react with NO to lead to ozone formation. With relatively low barriers, isomerization of the p-xylene bicyclic radicals to more stable epoxide radicals likely occurs, competing with O(2) addition to form bicyclic peroxy radicals. The study provides thermochemical and kinetic data for assessment of the photochemical production potential of ozone and formation of toxic products and secondary organic aerosol from p-xylene oxidation.     

Photoexcitation of dinucleoside radical cations: a time-dependent density functional study

The excited states of dinucleoside phosphates (dGpdG, dApdA, dApdT, TpdA, and dGpdT) in their cationic radical states were studied with time-dependent density functional theory (TD-DFT). The ground-state geometries of all the dinucleoside phosphate cation radicals considered, in their base stacked conformation, were optimized with the B3LYP/6-31G(d) method. Further, to take into account the effect of the aqueous environment surrounding the dinucleoside phosphates, the polarized continuum model (PCM) was considered and the excitation energies were computed by using the TD-B3LYP/6-31G(d) method. From this study, we find that the first transition in all the dinucleoside molecules involves hole transfer from base to base. dG*+pdG and dApdA*+ were found to have substantially lower first transition energies than others with two different DNA bases. Higher energy transitions involve base to sugar as well as base to base hole transfer. The calculated TD-B3LYP/6-31G(d) transition energies are in good agreement with previous calculations with CASSCF/CAS-PT2 level of theory. This TD-DFT work supports the experimental findings that sugar radicals formed upon photoexcitation of G*+ in gamma-irradiated DNA and suggests an explanation for the wavelength dependence found.     

The hydrolysis mechanism of the anticancer ruthenium drugs NAMI-A and ICR investigated by DFT-PCM calculations

(ImH)[trans-RuCl(4)(DMSO-S)(Im)], (Im = imidazole, DMSO-S = S-bonded dimethylsulfoxide), NAMI-A, is the first anticancer ruthenium compound that successfully completed Phase I clinical trials. NAMI-A shows a remarkable activity against lung metastases of solid tumors, but is not effective in the reduction of primary cancer. The structurally similar (ImH)[trans-RuCl(4)(Im)(2)], ICR (or KP418), and its indazole analog (KP1019) are promising candidate drugs in the treatment of colorectal cancers, but have no antimetastatic activity. Despite the pharmacological relevance of these compounds, no rationale has been furnished to explain their markedly different activity. While the nature of the chemical species responsible for their antimetastatic/anticancer activity has not been determined, it has been suggested that the difference between reduction potentials of NAMI-A and ICR may be the key to the different biological responses they induce. In this work, Density Functional Theory calculations were performed to investigate the hydrolysis of NAMI-A and ICR in both Ru(III) and Ru(II) oxidation states, up to the third aquation. In line with experimental findings, our calculations provide a picture of the hydrolysis of NAMI-A and ICR mainly as a stepwise loss of chloride ligands. While dissociation of Im is unlikely under neutral conditions, that of DMSO becomes competitive with the loss of chloride ions as the hydrolysis proceeds. Redox properties of NAMI-A and ICR and of their most relevant hydrolytic intermediates were also studied in order to monitor the effects of biological reductants on the mechanism of action. Our findings may contribute to the identification of the active compounds that interact with biological targets, and to explain the different biological activity of NAMI-A and ICR.     

Catalytic CO oxidation by a gold nanoparticle: a density functional study

Gold is usually considered very noble. It does not oxidize, and the surface of gold cannot adsorb most molecules from the gas phase. Yet it has been found that nanometer size gold particles on different oxide supports can act as catalysts even at or below room temperature. We present self-consistent density functional calculations showing that even an isolated Au10 cluster should be able to catalyze the CO oxidation reaction even below room temperature. We use the calculations to analyze the origin of this effect and suggest that the extraordinary reactivity can be traced back to special reaction geometries available at small particles in combination with an enhanced ability of low coordinated gold atoms to interact with molecules from the surroundings.     

Ethylene-styrene copolymerization with constrained geometry catalysts: a density functional study

A density functional theory (DFT) study of the ethylene-styrene copolymerization process with titanium-based constrained geometry catalyst (CGC) is presented. To establish the difference between simplified CGC or real CGC models, i.e., considering all ligands of the catalyst, we have performed calculations for ethylene and styrene insertions in both models. Thus, we have used two different DFT functional, BP86 and B3L YP along with two basis set, LANL 2DZ (without polarization functions) and DZVP (including polarization functions). We have noted certain differences between theoretical results published by other authors and our theoretical and experimental data.     

Copper impurities in bulk ZnO: a hybrid density functional study

Transition metal doping of ZnO is considered as a promising way to obtain a diluted magnetic semiconducting oxide. In this work we investigate copper doping of ZnO by means of density functional theory, using a hybrid exchange-correlation functional and a periodic approach with localized atomic basis functions. Isolated copper species, such as copper substitutional to zinc, Cu(s), and Cu interstitial, Cu(i), are analyzed in terms of transition energy levels and hyperfine coupling constants with reference to available spectroscopic data. We also examine the potential magnetic interaction between copper species, their interaction with oxygen vacancies, and the possibility of copper clustering. The relative stability of the various copper impurities considered in this study is finally compared on the basis of their formation energy at different oxygen chemical potentials and Fermi level values.     

烯丙醇与臭氧反应机理的密度泛函理论研究

应用密度泛函理论的MPW1K,BHandHLYP和MPWB1K方法,结合6-31+G(d,p)基组优化了烯丙醇与臭氧反应势能面上各驻点的几何构型,通过同一水平的振动频率分析确认了中间体和过渡态.反应路径上的驻点都在HL理论水平下进行单点能量校正,并进行了MPW1K/6-31+G(d,p)水平下的零点振动能校正(ZPE).对反应机理的详尽分析表明臭氧抽取烯丙醇羟基基团中H的通道的反应势垒比臭氧加合烯丙醇双键基团通道的反应势垒高,臭氧与烯丙醇双键加合生成臭氧化物为最可几反应路径.在加合反应历程中,氢迁移通道需经过氢迁移和离解等复杂过程,最终要产生少量的OH自由基,与烃烯类臭氧化反应产生大量OH自由基的结果相反.