Diana Cheshmedzhieva

Reactivity of Acetanilides in the Alkaline Hydrolysis Reaction: Theory vs. Experiment

The rate constants (at 25°C) for the alkaline hydrolysis of a series of seven acetanilide derivatives were determined experimentally. The series included the parent compound acetanilide and the following para-substituents: CH3, OCH3, NH2, CHO, COCH3 and NO2. The obtained kinetic data were then correlated with the following theoretically estimated reactivity indices: Mulliken and NBO atomic charges, the Parr electrophilicity index (ω), and the electrostatic potential at the carbon and nitrogen atoms of the reaction center (V C, V N). Very good correlation between the logarithm of the rate constant, ln k, and the ω values was established. Excellent correlations between V C and V N and ln k were found. The data obtained show that the model-independent electrostatic potential at the nuclei provides a reliable quantitative approach for describing the reactivity of organic compounds.

Assembly of New Merocyanine Chromophores with a 1,8-Naphthalimide Core by a New Method for the Synthesis of the Methine Function

A new method for the synthesis of the monomethine group using nitro as a leaving group in an SN-Ar reaction is described. A series of novel merocyanine dyes has been synthesised and their photophysical properties have been elucidated. The longest wavelength absorption occurs in the range 519–619 nm and the molar absorptivities vary with the substituents and are in the range 1000–47700 L mol–1 cm–1. The dyes show high chemical and photostability. One example from the series has the ability to distinguish methanol from ethanol. The introduction of a quinoid fragment into the structure leads to a pronounced intramolecular charge transfer and hence a noticeable positive solvatochromism. The structures and electronic properties of the compounds have been studied by density functional theory (DFT) and time-dependent DFT.

Competition between abiogenic Al 3+ and native Mg 2+ , Fe 2+ and Zn 2+ ions in protein binding sites: implications for aluminum toxicity

Abiogenic aluminum has been implicated in some health disorders in humans. Protein binding sites containing essential metals (mostly magnesium) have been detected as targets for the “alien” Al3+. However, the acute toxicity of aluminum is very low. Although a substantial body of information has been accumulated on the biochemistry of aluminum, the underlying mechanisms of its toxicity are still not fully understood. Several outstanding questions remain unanswered: (1) Why is the toxicity of aluminum, unlike that of other “alien” metal cations, relatively low? (2) Apart from Mg2+ active centers in proteins, how vulnerable are other essential metal binding sites to Al3+ attack? (3) Generally, what factors do govern the competition between ‘alien” Al3+ and cognate divalent metal cations in metalloproteins under physiologically relevant conditions? Here, we endeavor to answer these questions by studying the thermodynamic outcome of the competition between Al3+ and a series of biogenic metal cations, such as Mg2+, Fe2+ and Zn2+, in model protein binding sites of various structures, compositions, solvent exposure and charge states. Density functional theory calculations were employed in combination with polarizable continuum model computations. For the first time, the presence of different Al3+ soluble species at physiological pH was properly modeled in accordance with experimental observations. The results suggest that a combination of concentration and physicochemical factors renders the Al3+ → M2+ (M = Mg, Fe, Zn) substitution and subsequent metalloenzyme inhibition a low-occurrence event at ambient pH: the more active aluminum species, [Al(H2O)6]3+, presents in very minute quantities at physiological conditions, while the more abundant soluble aluminum hydrate, {[Al(OH−)4](H2O)2}−, appears to be thermodynamically incapable of substituting for the native cation.

Hydroxamic acid derivatives as histone deacetylase inhibitors: a DFT study of their tautomerism and metal affinities/selectivities

Hydroxamic acids are regarded as potent inhibitors of histone deacetylases (HDAC), and can therefore be used to reduce malignancy growth and size in affected organisms. Although there is a substantial body of information on the structures, syntheses, and biological activities of HDAC inhibitors, several important questions regarding their physicochemical properties and metal affinities/selectivities remain answered. First, how do the conformation and ionization of the hydroxamic group depend on its chemical composition and the dielectric properties of the medium? Second, how do these factors affect the affinities and selectivities of HDAC inhibitors for essential biogenic metal cations? Third, what is the preferred deprotonation site of the hydroxamic moiety and its mode of binding to the metal cation? The present work addressed these questions by performing density functional calculations combined with polarizable continuum model computations. The geometry, deprotonation pattern, metal-binding mode, and metal affinity/selectivity of SAHA, a typical HDAC inhibitor, were examined, and key factors affecting its ligation properties were elucidated. Sulfur- and selenium-containing analogs of SAHA were also modeled for the first time, and their potential as efficient metal-binding entities (to Mg2+, Fe2+, and Zn2+ cations) was assessed. The present calculations shed light on the thermodynamics of the binding of HDAC inhibitors to metal ions, and suggest techniques for enhancing their metal-ligating properties.

Hyperconjugative effects in π‐hydrogen bonding: Theory and experiment

Density functional theory computations with the B3LYP/6‐311++G(2df,2p) method and IR spectroscopy are employed in investigating the properties of twenty π‐hydrogen bonded complexes between substituted phenols and hexamethylbenzene. All complexes possess T‐shaped structures. The methyl hyperconjugative effects on interactions energies and OH stretching frequencies are estimated via comparisons with previously reported theoretical and experimental results for analogous phenol complexes with benzene. The theoretical computations provide excellent quantitative predictions of the OH stretching frequency shifts (ΔνOH) resulting from the hydrogen bonding. The ΔνOH shifts in the hexamethylbenzene complexes are approximately twice as large as the corresponding shifts for the benzene complexes. Hirshfeld charges, electrostatic potential at nuclei values, and molecular electrostatic potential maps are employed in gaining insights into the mechanisms of methyl hyperconjugative effects on complex formation.