Figure 4. Plot of the relation between p-phenols toxicity,
log(1/IC 50), and interaction energies,E int, of data sets A (black squares), B (red
circles) and C (blue triangles). Dashed lines correspond to linear
parameters in Table 2.
Finally, the cytotoxicity correlation with the interaction energy data,
Eint, (Table S1 in Supplementary information) as a
measure of the phenol reactivity[11] according to
Eq. (2) exhibit the best statistical parameters (Table 2, Fig. 4) for
the dataset A.
There are significant differences between the regression parameters of
the Eq. (2) for both A and B datasets. Except for Eint,
the B dataset ones are nearly doubled. In agreement with worse
statistical parameters for the B dataset, a similar relation holds for
their standard deviations as well. With few exceptions, the B dataset
cytotoxicity values are higher than the A ones for similar predictor
values whereas the C ones are even lower. The rightness of inclusion of
the iodine substituent into the A dataset is confirmed by comparing the
corresponding data evaluated by the Eq. (2) by using its regression
parameters both for A and B datasets (Table S3 of Supplementary
information).
We performed regression analysis for the predictor data of the
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 ) used by Selassie et
al. [2] as well. The obtained results for the
regression parameters of Eq. (2) and related statistical data are
presented in Table 2 and Figs. S4 – S7 of Supplementary information. In
all cases these variables offer much worse statistical parameters than
our predictors related to a Cu(II) probe. The distribution of A and B
dataset data is more chaotic despite the b parameter of the Eq. (2) for
both datasets is nearly identical.
Finally it can be concluded that the QSAR model based on
quantum-chemical calculations of the Cu(II) coordination ability of
p-substituted phenols offers much better results than classical
treatments.[2] The predictors based on the O → Cu
electron density transfer, such as copper charges and BCP electron
density Laplacian of the Cu-O bond in the2[Ph… Cu]2+complexes, as well as the corresponding interaction energy are able of a
very good toxicity prediction. The p-substituted phenols with electron
withdrawing and electron donating substituents must be treated
separately due to different linear dependencies of both groups.
Nevertheless, there may be more than one mechanism for various types of
toxicity as indicated by the phenols of the C dataset. Further
experimental as well as theoretical studies in this field are desirable.