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Anticancer Res. 2004 Sep-Oct;24(5A):3019-26.

Kinetic radical scavenging activity and cytotoxicity of 2-methoxy- and 2-t-butyl-substituted phenols and their dimers.

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Meikai University School of Dentistry, Saitama, Japan.


The dimers bis-EUG, bis-MMP, bis-BHA, bis-BMP and bis-DBP were synthesized from the monomers 4-allyl-2-methoxyphenol (EUG), 2-methoxy-4-methylphenol (MMP), 2-t-butyl-4-methoxyphenol (BHA), 2-t-butyl-4-methylphenol (BMP) and 2,4-di-t-butylphenol (DBP), respectively. The stoichiometric factors (n; number of free radicals trapped by one mole of phenolic moiety) of these compounds were determined by induction period methods with a kinetic approach in the 2'2-azobisisobutyronitrile (AIBN) and benzoyl peroxide (BPO) systems at 70 degrees C. The n values for bis-EUG, bis-MMP and bis-BHA were approximately two-fold greater than those for their monomers in both the AIBN and BPO systems, whereas the n values for bis-BMP and bis-DBP were identical to those of their monomers. bis-EUG, bis-MMP and bis-BHA, containing methoxy groups, were potent antioxidants. The n values (1.3-1.6) for EUG and MMP were considerably less than 2, as is commonly observed for the stoichiometric factors of phenolic compounds. The antiradical efficiencies against DPPH (diphenylpicrylhydrazyl) of the monomers and their dimers were also investigated, likewise indicating that bis-EUG, bis-MMP and bis-BHA were potent antioxidants. DBP and bis-DBP were less effective radical scavengers because of the steric factor of their bulky t-butyl groups. On the basis of cytotoxic activity against a human submandibular gland carcinoma cell line (HSG) and human gingival fibroblasts (HGF), these compounds could be classified into a high-activity group (DBP, bis-DBP and bis-BMP, with butylated hydroxytoluene (BHT) as a positive control) and a low-activity group (MMP, EUG, BHA, BMP, bis-BHA and bis-EUG). The cytotoxicity of EUG and BHA was markedly reduced by dimerization, whereas that of MMP was enhanced. The sensitivity index (ratio of 50% cytotoxic concentration for HGF cells to that for HSG cells) of EUG, MMP, bis-MMP and bis-BHA was approximately 9, 5, 7 and 2, respectively, whereas that of the other compounds was approximately 1. Potential mechanisms of cytotoxicity were assessed by PM3 semiempirical molecular orbital (MO) calculations. Tumor cells were highly sensitive to 2-methoxy-4-alkylphenols such as EUG and MMP, possibly due to the formation of cytotoxic quinone methide intermediates. In contrast, the high sensitivity index of bis-MMP may be related to the production of a highly reactive substance, CH3+, via oxidation. Structure-activity relationship (SAR ) models using PM3 calculations may be useful to predict biological activity during the development of potential anticancer drugs.

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