Investigation of the radical scavenging potential of vanillin-based pyrido-dipyrimidines: experimental and in silico approach.

Antioxidants have a significant contribution in the cell protection against free radicals which may induce oxidative stress, and permanently damage the cells causing different disorders such as tumors, degenerative diseases, and accelerated aging. Nowadays, a multi-functionalized heterocyclic framework plays an important role in drug development, and it is of great importance in organic synthesis and medicinal chemistry. Encouraged by the bioactivity of the pyrido-dipyrimidine scaffold and vanillin core, herein, we made an effort to thoroughly investigate the antioxidant potential of the vanillin-based pyrido-dipyrimidines A-E to reveal novel promising free radical inhibitors. The structural analysis and the antioxidant action of the investigated molecules were performed in silico by DFT calculations. Studied compounds were screened for their antioxidant capacity using in vitro ABTS and DPPH assays. All the investigated compounds showed remarkable antioxidant activity, especially derivative A exhibiting inhibition of free radicals at the IC50 value (ABTS and DPPH assay 0.1 mg ml-1 and 0.081 mg ml-1, respectively). Compound A has higher TEAC values implying its stronger antioxidant activity compared to a trolox standard. The applied calculation method and in vitro tests confirmed that compound A has a strong potential against free radicals and may be a novel candidate for application in antioxidant therapy.

Alizarin as a potential protector of proteins against damage caused by hydroperoxyl radical.

Alizarin is a natural anthraquinone molecule with moderate antioxidative capacity. Some earlier investigations indicated that it can inhibit osteosarcoma and breast carcinoma cell proliferation by inhibiting of phosphorylation process of ERK protein (extracellular signal-regulated kinases). Several mechanisms of deactivation of one of the most reactive oxygen species, hydroperoxyl radical, by alizarin are estimated: hydrogen atom abstraction (HAA), radical adduct formation (RAF), and single electron transfer (SET). The plausibility of those mechanisms is estimated using density functional theory. The obtained results indicated HAA as the only thermodynamically plausible mechanism. For that purpose, two possible mechanistic pathways for hydrogen atom abstraction are studied in detail: hydrogen atom transfer (HAT) and proton-coupled electron transfer (PCET). Water and benzene are used as models of solvents with opposite polarity. To examine the difference between HAT and PCET is used kinetical approach based on the Transition state theory (TST) and determined rate constants (k). Important data used for a distinction between HAT and PCET mechanisms are obtained by applying the Quantum Theory of Atoms in Molecules (QTAIM), and by the analysis of single occupied molecular orbitals (SOMOs) in transition states for two examined mechanisms. The molecular docking analysis and molecular dynamic are used to predict the most probable positions of binding of alizarin to the sequence of ApoB-100 protein, a protein component of plasma low-density lipoproteins (LDL). It is found that alizarin links the nitrated polypeptide forming the π-π interactions with the amino acids Phenylalanine and Nitrotyrosine. The ability of alizarin to scavenge hydroperoxyl radical when it is in a sandwich structure between the polypeptide and radical species, as the operative reaction mechanism, is not significantly changed concerning its antioxidant capacity in the absence of polypeptide. Therefore, alizarin can protect the polypeptide from harmful hydroperoxyl radical attack, positioning itself between the polypeptide chain and the reactive oxygen species.

Importance of hydrogen bonding and aromaticity indices in QSAR modeling of the antioxidative capacity of selected (poly)phenolic antioxidants.

The quantitative structure-activity relationship (QSAR) models for predicting antioxidative capacity of 21 structurally similar natural and synthetic phenolic antioxidants was considered. The one-, two- and three-descriptor QSAR models were developed. For this purpose the literature data on the vitamin C equivalent antioxidative capacity (VCEAC) values were used as experimental descriptor of antioxidative capacity. Some thermodynamic and aromaticity properties, as well as the natural bond analysis (NBO) based quantities aimed at measuring the strength of intramolecular hydrogen bonds, were used as independent variables. It was examined whether a combination of these variables can yield a mathematical function that is in good correlation with the VCEAC values. It was shown that a combination of a certain thermodynamic descriptor (related to the single proton loss electron transfer mechanism) with the NBO-based quantities results in several two-descriptor models with the correlation coefficient greater than 0.950. Thus, a significant influence of internal hydrogen bonds on the antioxidative capacity of the studied molecules was confirmed. The best correlation with the VCEAC values was achieved within a three-descriptor QSAR model. This model was obtained by including a magnetic aromaticity index. It was found that aromaticity has only secondary effects on the antioxidative capacity.

Free radical scavenging and COX-2 inhibition by simple colon metabolites of polyphenols: A theoretical approach.

Free radical scavenging and inhibitory potency against cyclooxygenase-2 (COX-2) by two abundant colon metabolites of polyphenols, i.e., 3-hydroxyphenylacetic acid (3-HPAA) and 4-hydroxyphenylpropionic acid (4-HPPA) were theoretically studied. Different free radical scavenging mechanisms are investigated in water and pentyl ethanoate as a solvent. By considering electronic properties of scavenged free radicals, hydrogen atom transfer (HAT) and sequential proton loss electron transfer (SPLET) mechanisms are found to be thermodynamically probable and competitive processes in both media. The Gibbs free energy change for reaction of inactivation of free radicals indicates 3-HPAA and 4-HPPA as potent scavengers. Their reactivity toward free radicals was predicted to decrease as follows: hydroxyl>>alkoxyls>phenoxyl≈peroxyls>>superoxide. Shown free radical scavenging potency of 3-HPAA and 4-HPPA along with their high µM concentration produced by microbial colon degradation of polyphenols could enable at least in situ inactivation of free radicals. Docking analysis with structural forms of 3-HPAA and 4-HPPA indicates dianionic ligands as potent inhibitors of COX-2, an inducible enzyme involved in colon carcinogenesis. Obtained results suggest that suppressing levels of free radicals and COX-2 could be achieved by 3-HPAA and 4-HPPA indicating that these compounds may contribute to reduced risk of colon cancer development.

Application of comparative vibrational spectroscopic and mechanistic studies in analysis of fisetin structure.

This paper addresses experimental and theoretical research in fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one) structure by means of experimental IR and Raman spectroscopies and mechanistic calculations. Density Functional Theory calculations, with M05-2X functional and the 6-311+G (2df, p) basis set implemented in the Gaussian 09 package, are performed with the aim to support molecular structure, vibrational bands' positions and their intensities. Potential energy distribution (PED) values and the description of the largest vibrational contributions to the normal modes are calculated. The most intense bands appear in the 1650-1500 cm(-1) wavenumber region. This region involves a combination of the CO, C2C3 and C-C stretching vibrational modes. Most of the bands in the 1500-1000 cm(-1) range involve C-C stretching, O-C stretching and in-plane C-C-H, C-O-H, C-C-O and C-C-C bending vibrations of the rings. The region below 1000 cm(-1) is characteristic to the combination of in plane C-C-C-H, H-C-C-H, C-C-C-C, C-C-O-C and out of plane O-C-C-C, C-C-O-C, C-C-C-C torsional modes. The Raman spectra of baicalein and quercetin were used for qualitative comparison with fisetin spectrum and verification of band assignments. The applied detailed vibrational spectral analysis and the assignments of the bands, proposed on the basis of fundamentals, reproduced the experimental results with high degree of accuracy.

Triplet fluoranthenes: aromaticity versus unpaired electrons.

Three fluoranthenes and one substituted fluoranthene, 2,2-dimethyl-2H-dibenzo[cd,k]fluoranthene, were investigated using the unrestricted symmetry-broken and complete active space methods. It was shown that four Kekuléan hydrocarbons are diradicals, implying that their ground state is a triplet. In the energetically less favorable singlet state these hydrocarbons exhibit pronounced diradical character. This occurance is explained with the tendency of the investigated molecules to delocalize their π-electrons. This leads to aromatic stabilization which is stronger than destabilization due to unpaired electrons. Our results for 2,2-dimethyl-2H-dibenzo[cd,k]fluoranthene are in excellent accord with experimental findings of McMaster et al. concerning this compound.

Correlations between local aromaticity indices of bipartite conjugated hydrocarbons.

Local aromaticity in rings of conjugated hydrocarbons can be measured in a variety of ways. In the present paper, we concentrate on two of these, namely, EC, i.e., the pi-electron content or pi-electron partition, and ef, the energy effect of cycles. For the central ring in five bipartite conjugated hydrocarbons (anthracene, triphenylene, perylene, coronene, and biphenylene), it was found that EC and ef values are modified in a consistent and predictable manner by annelation with benzenoid rings. Equations are presented for computing EC and ef values for the central ring in terms of three integers representing the numbers of annelated benzenoid rings (A, L, and G for angular, linear, and geminal annelation, respectively). The coefficients of A and G are positive (A > G) and the coefficient of L is negative for benzenoids, but for biphenylene, the situation is reversed for coefficients in the correlation for ef values.