1 Introduction
Phenolic compounds and their derivatives are constituents of numerous synthetic and natural chemicals such as drugs, cosmetics, dyes, agricultural products, pesticides, food additives etc. Their properties have been frequently studied at the molecular and cellular level. Phenolic-based compounds provide an excellent opportunity to examine their biological activities and to analyze corresponding mechanistic details in a comparative fashion using the quantitative structure activity relationship (QSAR) paradigm. It has been useful in elucidating the mechanisms of chemical–biological interactions in various biomolecules, particularly enzymes, membranes, organelles and cells.[1]
Selassie et al .[2] studied the cytotoxicity of a series of 69 simple phenols in a fast growing murine leukemia L1210 cell line. They developed a Quantitative Structure–Activity Relationship (QSAR) model where the cytotoxicity of the substituted phenol was evaluated as log(1/IC 50), withIC 50 being its concentration that inhibited cell growth by 50%. These values were correlated with Brown-Hammett parameters (σ +), the HOMO–LUMO energy difference (L–H gap), the logarithmic n-octanol - water partition coefficients (log P ) and homolytic bond dissociation energies (BDE ). Phenols with electron withdrawing substituents were excluded from the analyses. BDE values were calculated at B3LYP/6-31G**//AM1 level of theory with effective core potentials used for bromine- and iodine-substituted molecules. L-H gap values were obtained by the semiempirical AM1 method only. Despite these restrictions, the developed QSAR models granted surprisingly good results with 17 – 27 outliers depending on the descriptors used. It seems that the above mentioned cytotoxicity descriptors cannot produce better results.
Alagona and Ghio[3] evaluated the antioxidant activity of various sites of prenylated pterocarpans according to their Cu2+ coordination ability using the metal ion affinity (MIA ) values determined by B3LYP calculations. Spin density of the cation upon ligand coordination became negligibly low, whereas the ligand spin density approached 1. Thus, the ligand was oxidized to a radical cation (Ligand•+), while Cu(II) was reduced to Cu(I). In agreement with experimental investigations, the higher antioxidant activity of individual compounds and their reaction sites can be assigned to higher MIA values and higher reducing character towards Cu(II). The Cu2+ ion serves as a probe to estimate the extent of the electron density transfer only and the optimized structures need not correspond to any real complex. Mammino[4] analogously tested antioxidant ability of various sites of hyperjovinol A. Another modification of the above-mentioned method by including Laplacians at Cu-N bond critical points (BCP) as the measure of the corresponding electron density transfer has been used for both N centres of a series ofpara -phenylene diamine antioxidants.[5]
Other 1st row transition metal ions were also used in the role of similar probes for the compounds with oxygen active sites. B3LYP, M06-2X, BHandHLYP, MPWLYP1M and G96LYP methods were used to study antioxidant properties of kanakugiol through its Cu(II) and Co(II) coordination ability[6] as well as lucidone, linderone and methyllinderone through their Fe(II) coordination ability.[7] Subsequently the authors continued in studying antioxidant properties of butein and homobutein[8], chalcone derivatives kanakugiol and pedicellin[9] by considering their Fe(II) and Fe(III) coordination ability using the B3LYP method. A systematic B3LYP study of a series of para-phenylene diamine antioxidants with the late 1st row transition metals in various spin states[10] has shown that using these M(II) probes yield very similar results of antioxidant effectiveness.
This method was used for the relative cytotoxicity estimation of various sites of model rutile nanoparticles as well.[11]It was shown that the experimentally observed higher cytotoxicity of rod-like nanoparticles in comparison with the spherical ones might be explained by the higher electron density transfer to the interacting cells (as indicated by the extent of the electron density transfer to a Cu2+ probe), whereas MIA reflects the reactivity of individual active sites. The aim of our recent study is the application of this method to predict the cytotoxicity ofp -substituted phenols. Our results will be compared with standard QSAR correlations used by Selassie et al .[2]