Relationship between phenol-induced cytotoxicity and experimental inhibition rate constant or a theoretical parameter.

We synthesized various dimer forms of 2-methoxyphenols and 2-tert-butylphenols, as dimers such as curcumin exhibit potent antioxidant and anti-inflammatory activity. We investigated the QSARs between the cytotoxicity and independent variables; kinetic parameters (inhibition rate constant (kinh/kp), stoichiometric factor (n)) or DFT-based theoretical parameters (i.e. phenolic O-H bond dissociation enthalpy (BDE), ionization potential according to Koopman's theorem (IP), LUMO, absolute hardness (η), electronegativity (χ) and electrophilicity (ω)) for 2-methoxyphenols and 2- tert- or 2,6-di-tert-butylphenols. The cytotoxicity of these phenols against human tumor cells (HSG, HL60) and/or human gingival fibroblasts (HGF) showed a marked negative linear relationship to kinh/kp, suggesting that the cytotoxicity of phenols may be related to radical reactions. By contrast, a linear relationship between the cytotoxicity and η-term was demonstrated; 2-methoxyphenols showed a negative slope, whereas 2-tert- or 2,6-di-tert-butylphenols showed a positive slope. Also, the cytotoxicity of tert-butylphenols was linearly dependent on the LUMO-term, showing a positive slope. The cytotoxicity of methoxy-substituted monophenols toward both HSG and HGF cells was related to both log P and η- terms. Also, that of X-phenols toward murine L-1210 cells was related to both log P and η or IP-terms, determined from a dataset reported by Zhang et al., 1998. It was concluded that the phenol-induced cytotoxicity was attributable to radical reactions resulting from the terms (kinh/kp, IP, η, and LUMO) in QSAR. The LUMO-dependent cytotoxicity of 2-tert- or 2,6-di-tert-butylphenols may be related to their quinone oxidation products. Experimental and theoretical parameters provide a useful approach for analysis of the cytotoxicity for phenolic compounds.