Luminescent and DFT Study of Keto-Enol Tautomers of 5-Fluorouracil and Its Derivatives in Aqueous Solutions.

Fluorescence (FL) spectra were recorded and identified for the following 5-fluorouracil (FU) tautomers: 5-fluoropyrimidine-2,4(1H,3H)-dione (A), 5-fluoro-2-hydroxypyrimidine-4(3H)-one (B), and 5-fluoro-4-hydroxypyrimidine-2(1H)-one (D), as well as the corresponding tautomers A and D of 1-(tetrahydrofuranyl-2)-5-fluorouracil and 1-methyl-5-fluorouracil, tautomers A and B of 3-methyl-5-fluorouracil, and the diketo tautomer of 1,3-dimethyl-5-fluorouracil. It was shown that the FL of rare tautomers of FU derivatives occurs by the excitation of uracil homoassociates followed by intramolecular proton transfer (IPT), formation of a pair of rare tautomers, and radiative deactivation of one of them. The FL quantum yields φi were estimated. In the case of rare tautomers, the φi value includes the probability of IPT in the homoassociate, and density functional theory calculations in the TPSSTPSS/6-311+G(d,p) approximation were used to determine the relative energies of tautomers, associated FU forms, and their spectral properties that agree with the observed luminescence pattern.

Effects of novel hexahydropyrimidine derivatives as potential ligands of M1 muscarinic acetylcholine receptor on cognitive function, hypoxia-induced lethality, and oxidative stress in rodents.

The neurodegenerative diseases have a complex pathogenetic mechanism comprising oxidative stress and receptor system dysfunction caused by various damaging factors such as, for example, brain hypoxia. The purpose of this study was to elucidate the influence of hexahydropyrimidine derivatives on learning, memory, and orientation and locomotor activities in the passive avoidance (PA) and open field (OF) tests and to evaluate these compounds for their potential antihypoxic and antioxidant action on normobaric hypercapnic hypoxia and toxic hypoxia models. We demonstrated that compounds 1a and 1e administered as a single 100 mg/kg dose (p.o.) one hour before the tests increased the latency time to enter the dark compartment for the first time and reduced the time spent in the dark compartment on the 2nd, 7th, and 14th days of PAT and increased the number of squares crossed and hole-pokings in the OF test. It was also shown that single administration of compounds 1a and 1e (in 100 mg/kg dose, p.o.) one hour before generation of hypoxia increased the life span of mice under normobaric hypoxia by 30% (P < 0.05) and, after injection of sodium nitroprusside, they decreased the malondialdehyde (MDA) level and increased the catalase level in the brain of mice. According to molecular docking results, compounds 1а and 1е are bound in the orthosteric active site of M1 muscarinic receptor via supramolecular interactions with a number of functional amino acids. The results indicate that hexahydropyrimidine derivatives have a beneficial effect on the memory, learning processes, and orientation and locomotor activities of rats in an unfamiliar environment and exhibit antihypoxic and antioxidant activities under hypoxia in mice. The cognitive enhancement can be mediated by the effect of lead compounds on the M1 muscarinic acetylcholine receptor.

Controlled stabilization of anionic forms of the uracil derivatives: A DFT study.

Relative stabilities of the N1/N3/О5/О6 anions of 42 substituted uracils in gas phase and aqueous solutions have been theoretically studied using approximation IEFPCM (SMD) - TPSS/aug-cc-pVTZ. The specific solvation of uracil and its anions has been simulated with the first hydrate shell made up with 5 water molecules. The nonspecific solvation has been accounted in terms of the SMD model. We have found a series of relative stability under conditions of both specific and nonspecific hydration. The series is ranked according to the increase of the relative stability of the N3 anion. In gas phase, the N1 anion is significantly more stable than its N3 counterpart: the ΔGgas values vary in the range from 19.54 (5OH6СН3U) to 83.14 (5NO26NH2U) kJ/mol that is caused by a more effective delocalization of the excess charge through the uracil framework in the N1 anion. The hydration pronouncedly diminishes ΔG to the range from -0.02 (5OH6СН3U) to 38.16 (5Br6NO2U) kJ/mol due to the fact that the polar solvent is prone to stabilize more polar anionic states of uracils. Therefore, less polar uracil anions are more stable. We have defined the main factor influencing the N1/N3/О5/О6 distribution of anions, viz. the presence of the substituents in 5 and 6 positions of the pyrimidine ring. Herewith, the most favorable mechanism of the influence of 5-substituents has been previously defined as resonant whereas, as we found in this work, the inductive mechanism is more pronounced in the case of 6-substituents.

Polyfluorinated salicylic acid derivatives as analogs of known drugs: Synthesis, molecular docking and biological evaluation.

We have developed the convenient methods for synthesis of polyfluorosalicylic acids and their derivatives. For the first time the biological properties of polyfluorosalicylates were investigated in vitro (permeability through the biological membranes, COX-1 inhibitory action) and in vivo (anti-inflammatory, analgesic activities, acute toxicity). Molecular docking of polyfluorinated salicylates confirmed in vitro and in vivo experiments.

Impact of chirality on the photoinduced charge transfer in linked systems containing naproxen enantiomers.

The model reaction of photoinduced donor-acceptor interaction in linked systems (dyads) has been used to study the comparative reactivity of a well-known anti-inflammatory drug, (S)-naproxen (NPX) and its (R)-isomer. (R)- or (S)-NPX in these dyads is linked to (S)-N-methylpyrrolidine (Pyr) using a linear or cyclic amino acid bridge (AA or CyAA), to give (R)-/(S)-NPX-AA-(S)-Pyr flexible and (R)-/(S)-NPX-CyAA-(S)-Pyr rigid dyads. The donor-acceptor interaction is reminiscent of the binding (partial charge transfer, CT) and electron transfer (ET) processes involved in the extensively studied inhibition of the cyclooxygenase enzymes (COXs) by the NPX enantiomers. Besides that, both optical isomers undergo oxidative metabolism by enzymes from the P450 family, which also includes ET. The scheme proposed for the excitation quenching of the (R)- and (S)-NPX excited state in these dyads is based on the joint analysis of the chemically induced dynamic nuclear polarization (CIDNP) and fluorescence data. The (1)H CIDNP effects in this system appear in the back electron transfer in the biradical-zwitterion (BZ), which is formed via dyad photoirradiation. The rate constants of individual steps in the proposed scheme and the fluorescence quantum yields of the local excited (LE) states and exciplexes show stereoselectivity. It depends on the bridge's length, structure and solvent polarity. The CIDNP effects (experimental and calculated) also demonstrate stereodifferentiation. The exciplex quantum yields and the rates of formation are larger for the dyads containing (R)-NPX, which let us suggest a higher contribution from the CT processes with the (R)-optical isomer.

Ozone addition to C60 and C70 fullerenes: a DFT study.

Three modes of synchronous ozone addition ([6.6]-, [5.6]-, and 1,4-addition) to C(60) fullerene and three modes of ozone addition to C(70) (ab-, cc-, and de-addition) have been studied using density functional theory calculations. Comparison of activation enthalpies shows that in the case of C(60), [6.6]-addition of ozone is the most favorable energetically and occurs without a barrier. In the case of the C(70) fullerene, additions to ab- and cc-bonds are the most favorable. The initial step of interaction between a C(60)/C(70) and O(3) is the formation of a molecular complex, which then converts into a primary ozonide. The calculated rate constant of the [6.6]-addition to the C(60) fullerene according to the proposed scheme is 3.90 x 10(6)L mol(-1)s(-1), which corresponds well to the experimental value.