Complexation of norfloxacin with DNA in the presence of caffeine

1H NMR spectroscopy (500 MHz) has been used to quantify the complexation of the antibacterial antibiotic Norfloxacin (NOR) with DNA in the presence of Caffeine (CAF). Separate studies have been made for the self-association of NOR, its hetero-association with CAF and complexation with a model self-complementary DNA tetramer, 5′-d(TpGpCpA), in order to determine the equilibrium parameters (induced chemical shifts, association constants, enthalpy and entropy) of the two-component mixtures to aid the analysis of the three-component systems. Investigations of the self-association of NOR and its hetero-association with CAF show that the aggregation of NOR molecules and association with CAF in solution are driven by the stacking of aromatic chromophores. The complexation of NOR with d(TGCA) has been analysed in terms of intercalation with the double-stranded form and non-intercalative binding with the single-stranded form of DNA. Investigations of the competitive binding of NOR and CAF with DNA show that at physiological concentrations of NOR (μM) and CAF (mM) the dominant mechanism influencing the affinity of NOR with DNA is the displacement of bound NOR molecules from DNA due to CAF–DNA complexation (i.e. the protector action of Caffeine)

Stochastic models (cooperative and non-cooperative) for NMR analysis of the hetero-association of aromatic molecules in aqueous solution

Stochastic cooperative (STOCH-C) and non-cooperative (STOCH-NC) models have been developed for NMR analysis of the hetero-association of aromatic compounds in solution, in order to take into account all physically meaningful association reactions of molecules in which there are no limitations on the lengths of the aggregates and complexes. These algorithmical approaches are compared with previously published basic (BASE) and generalized (GEN) analytical statistical thermodynamical models of hetero-association of biologically active aromatic molecules using the same sets of published NMR data measured under the same solution conditions (0.1 M phosphate buffer, pD = 7.1, T = 298 K). It is shown that, within experimental errors, the BASE analytical model may be used to describe molecular systems characterized by relatively small contributions of hetero-association reactions, whereas the GEN model may be applied to hetero-association reactions of any aromatic compound with different self-association properties. The STOCH-C computational algorithm enabled the effect on hetero-association of the interactions of molecules with different cooperativity parameters of self-association to be estimated for the first time and it is proposed that the algorithm for the stochastic models has great potential for detailed investigation and understanding of the interactions of aromatic molecules in solution

Effect of a mixture of caffeine and nicotinamide on the solubility of vitamin (B2) in aqueous solution

The effect of caffeine (CAF) and nicotinamide (NMD) on the solubility of a vitamin B2 derivative (FMN) has been evaluated for mixtures containing either a single hydrotrope (CAF or NMD) or the two hydrotropes simultaneously. A model for analysis of ternary systems, which takes into account all possible complexes between the molecules, has been developed and tested with experimental NMR data on the three-component mixture FMN–CAF–NMD. The results indicate that special attention should be given to the concentration of a hydrotropic agent used to enhance the solubility of a particular drug. A decrease in the efficacy of solubility of the vitamin on addition of large amounts of hydrotropic agent is expected in the two-component systems due to the increased proportion of self-association of the hydrotrope. It is found that a mixture of two hydrotropic agents leads to an increase in the solubility of the vitamin in three-component compared to the two-component system. Rather than using just one hydrotropic agent, it is proposed that a strategy for optimising the solubility of aromatic drugs is to use a mixture of hydrotropic agents

Hydration change on complexation of aromatic ligands with DNA: molecular dynamics simulations

Aim. Analysis of the hydration changes at formation of DNA complexes with biologically active aromatic compounds (BAC): antibiotics actinomycin D, daunomycin, nogalamycin, novantrone and mutagens ethidium bromide and proflavine. Methods. Molecular dynamics simulations. Results. The hydration indexes for double-helical DNA and ligands in a free and complexed states were calculated. A critical analysis of modern ideas about changing water environment at binding of aromatic ligands to DNA was performed. Conclusions. It is shown that upon binding of aromatic BAC with DNA a significant (from 2.6 for novantrone to 13.1 for actinomycin D) liberation of water molecules out of hydration shells with the disruption of hydrogen bonds takes place.Цель. Исследование изменения гидратации при образовании комплексов с ДНК ароматических биологически активных соединений (БАС): антибиотиков актиномицина D, дауномицина, ногаламицина, новантрона и мутагенов бромистого этидия и профлавина. Методы. Молекулярная динамика. Результаты. Вычислены гидратационные индексы для двуспиральной ДНК и лигандов в свободном состоянии и в составе комплекса. Проведен критический анализ современных представлений об изменении водного окружения при связывании с ДНК ароматических лигандов. Выводы. Показано, что при взаимодействии ароматических БАС с ДНК происходит значительное (от 2,6 для новантрона до 13,1 для актиномицина D) высвобождение молекул воды гидратных оболочек с разрывом водородных связей.Мета. Дослідження зміни гідратації при утворенні комплексів з ДНК ароматичних біологічно активних сполук (БАС): антибіотиків актиноміцину D, дауноміцину, ногаламіцину, новантрону і мутагенів бромистого етидію і профлавіну. Методи. Молекулярна динаміка. Результати. Обчислено гідратаційні індекси для двоспіральної ДНК і лігандів у вільному стані та у складі комплексу. Проведено критичний аналіз сучасних уявлень щодо зміни водного оточення при зв’язуванні з ДНК ароматичних лігандів. Висновки. Показано, що при взаємодії ароматичних БАС з ДНК відбувається значне (від 2,6 для новантрону до 13,1 для актиноміцину D) вивільнення молекул води гідратних оболонок з розривом водневих зв’язків

1H NMR determination of the self-association of an acridine homodimer and its complexation with ethidium bromide in aqueous solution

1H NMR spectroscopy (500MHz) has been used to investigate the self-association in aqueous buffered solution of a bis-intercalator, Acridine Homodimer (AcrH), and its hetero-association with the aromatic dye, Ethidium Bromide (EB). The equilibrium constants and thermodynamical parameters (enthalpy and entropy) of self-association have been determined from the observed concentration and temperature dependences of chemical shifts of AcrH protons and the results are consistent with a model consisting of at least four distinct forms of AcrH molecules in solution: unfolded (U), folded (F), a dimer formed from two folded molecules (F2) and a trimer formed from three folded molecules (F3). It has also been shown that Ethidium Bromide complexes strongly to the dimer form (F2) of the bis-acridine molecule, AcrH. Comparison of the calculated association parameters of AcrH with the previously studied Ethidium Homodimer (EBH) revealed a correlation between the effectiveness of complexation and the length of chain connecting the chromophores of a bis-intercalator

Hetero-association of aromatic molecules in aqueous solution

Knowledge of the physical chemistry of small molecules complexation (the hetero-association) in aqueous solution is increasingly important in view of the rapidly emerging branch of supramolecular chemistry dealing with the formation of heterogeneous polymeric structures having specific functional roles. In this paper, the 50-year history of scientific studies of hetero-association of heterocyclic aromatic molecules in aqueous solution has been reviewed. Some important correlations of structural and thermodynamic parameters of complexation have been reported based on large data-set of hetero-association parameters accumulated to date. The fundamental problem of ‘energetic composition’ of π-stacking is extensively discussed. The review has shown that there are some gaps in our understanding of heteroassociation, which provides a challenge for further studies in this are

On the origin of the decrease in stability of the DNA hairpin d(GCGAAGC) on complexation with aromatic drugs

Molecular dynamics simulations of drug–DNA complexes have been carried out in order to explain the experimentally observed decrease in thermal stability of the DNA hairpin d(GCGAAGC) on binding the aromatic drug molecules, daunomycin, ethidium bromide, novantrone and proflavine. This complexation behavior is in contrast to the stabilizing effect of the same aromatic drug molecules on DNA duplexes. Analysis of the energy parameters and the hydration properties of the complexes shows that the main factor correlating with the decrease in melting temperatures of the drug–hairpin complexes is the number of water bridges, with a reduction of at least 40% on ligand binding

Investigation of the complexation of the anti-cancer drug novantrone with the hairpin structure of the deoxyheptanucleotide 5'-d(GpCpGpApApGpC)

In aqueous solution the deoxyheptanucleotide, 5′-d(GpCpGpApApGpC), exists as a very stable hairpin structure in equilibrium with small proportions of the single-stranded and duplex forms. Complexation of the anti-cancer drug novantrone (mitoxantrone) with the DNA heptamer was investigated by one- and two-dimensional 500 MHz 1H NMR spectroscopy (2M-TOCSY, 2M-NOESY) and molecular dynamics simulations. The proton chemical shifts of NOV in mixed solutions with the heptamer were measured as a function of concentration and temperature and the equilibrium association parameters were determined for complexation of NOV with the three forms of the heptamer. The spatial structure of the complex of the antibiotic with the hairpin form of the heptamer was built on the basis of 2D-NOE data. The conformational dynamics of the complex and its interaction with the water environment were investigated by molecular dynamics methods. The results suggest that NOV complexes with the hairpin form of the heptamer in solution by intercalation. Complexation of NOV with the hairpin stem results in a disruption of about one half of the intramolecular water bridges of the hairpin, which is considered to be the main reason for the observed decrease in the thermodynamical stability of the hairpin on binding with the ligand