Predicting the biological activities of 2-methoxyphenol antioxidants: effects of dimers.

Selective cyclooxygenase (COX)-2 inhibitors have attracted much attention in relation to the design of non-steroidal anti-inflammatory agents (NSAIDs). The relationship between experimentally derived data on the antioxidant capacity, cytotoxicity and COX-2 inhibition for a range of 2-methoxyphenols and their calculated descriptors was investigated.

METHODS

Quantitative structure-activity relationship (QSAR) studies were performed on a series of 2-methoxyphenols that act as COX-2 inhibitors using electronic descriptors, such as the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), ionization potential (IP), chemical hardness (q), and electronegativity (chi), which were calculated by the CONFLEXIPM3 method. The antioxidant capacity of a range of 2-methoxyphenols was evaluated by 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity, and the anti-peroxy radical activity (stoichiometric factor, n) was determined by the induction period method in the polymerization of methyl methacrylate (MMA) initiated by thermal decomposition of benzoyl peroxide (BPO). The 50% cytotoxic concentration (CC50) against human submandibular gland tumor cell line (HSG) was determined by the MTT method.

RESULTS

Cytotoxicity declined in the order of curcumin > dehydrodiisoeugenol > isoeugenol >bis-MMP > eugenol > ferulic acid > 2-methoxy-4-methylphenol (MMP) > bis-eugenol > bis-ferulic acid. The inhibitory effects on LPS-induced COX-2 gene expression in RAW 264.7 cells were determined by Northern blot assay. The majority of 2-methoxyphenols studied were COX-2 inhibitors. In particular, dehydrodiisoeugenol was a potent inhibitor, followed by bis-ferulic acid and curcumin. A linear relationship between anti-DPPH radical activity (log 1/IC50) and IP for 2-methoxyphenols except for dehydrodiisoeugenol was observed (r2=0.768.) The n for methoxyphenols was less than 2 in most cases. A linear relationship (r(2)=0.713) between the log (1/CC50) and the r1-term except for ferulic acid was observed. COX-2 inhibition, except for hesperetin, was related to the chi-term (r(2)=0.685).

CONCLUSIONS

It may be possible to predict the mechanism responsible for the biological activities of 2-methoxyphenols.