methyl-3-methoxy-4-hydroxystyryl-ketone and isoeugenol

Twenty-eight compounds related to dehydrozingerone (1), isoeugenol (3), and 2-hydroxychalcone (4) were synthesized and evaluated in vitro against human tumor cell replication. Except for isoeugenol analogues 27-35, most compounds exhibited moderate or strong cytotoxic activity against KB, KB-VCR (a multidrug-resistant derivative), and A549 cell lines. In particular, chalcone 15 showed significant cytotoxic activity against the A549 cell line with an IC50 value of 0.6 microg/mL. Furthermore, dehydrozingerone analogue 11 and chalcones 16 and 17 showed significant and similar cytotoxic activity against both KB (IC50 values of 2.0, 1.0, and 2.0 microg/mL, respectively) and KB-VCR (IC50 values of 1.9, 1.0, and 2.0 microg/mL, respectively) cells, suggesting that they are not substrates for the P-glycoprotein drug efflux pump.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chalcones; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Eugenol; Humans; Inhibitory Concentration 50; Molecular Structure; Styrenes; Tumor Cells, Cultured

We have investigated the effect of phenolic antioxidants on cisplatin-induced cytotoxicity in vero (African Green Monkey Kidney) cells and in rat renal cortical slices in vitro, and on cisplatin-induced nephrotoxicity in rats in vivo. Incubation of cisplatin with vero cells resulted in time- and concentration-dependent cytotoxicity, as characterized by decreased tryphan blue exclusion (TBE) and increased release of lactate dehydrogenase (LDH) into the medium. Cisplatin also caused reduction of glutathione (GSH) in a concentration-dependent manner. In the rat renal cortical slices model, incubation of cisplatin for 120 min caused an increase in malondialdehyde (MDA), a decrease in GSH and inhibited p-aminohippurate (PAH) uptake in a concentration-dependent manner. Among phenolic antioxidants, isoeugenol (IG) was found to be more active against cisplatin-induced cytotoxicity in vero cells as well as in rat renal cortical slices than eugenol (EG) and dehydrozingerone (DZ). However none of the test compounds were able to arrest the reduction of the GSH content induced by cisplatin in either the vero cells or the renal cortical slice model. Administration of cisplatin (3 mg/kg) i.p. to rats resulted in significant reduction of body weight, and elevation of blood urea nitrogen (BUN) and serum creatinine. Treatment with IG 10 mg/kg i.p. 1 h before cisplatin resulted in partial but significant protection against the cisplatin-induced reduction of body weight, and elevation of BUN and serum creatinine, the protection being 34, 46, and 62%, respectively. EG and DZ (10 mg/kg, i.p.) were found to be inactive in vivo. Because IG is a potent free radical scavenger and protects against cisplatin-induced toxicitiy, the present results have many clinical implications in chemotherapy and thus warrants further investigation.

Topics: Animals; Antineoplastic Agents; Antioxidants; Blood Urea Nitrogen; Cell Division; Cells, Cultured; Chlorocebus aethiops; Cisplatin; Creatinine; Eugenol; Kidney Cortex; Kidney Diseases; Male; Phenols; Rats; Rats, Wistar; Styrenes; Vero Cells

A few structurally related phenols, dehydrozingerone (DZ), bromopentenone (BP), eugenol (EG) and isoeugenol (IEG), derived from plant products show antioxidant properties by inhibiting lipid peroxidation in membrane models. The phenoxyl radicals produced by the scavenging of free radicals during the inhibition of lipid peroxidation, were also generated by specific one-electron oxidants using pulse radiolysis. The radical lifetimes (second order rate constants for radical-radical reactions), reactivities with hydroxyl and model peroxyl radicals and the one-electron reduction potentials with respect to the standard couples were quantified. These results along with their lipophilicity data were correlated with their antioxidant activity (IC50 values).

Topics: Antioxidants; Azides; Eugenol; Free Radical Scavengers; Free Radicals; Hydrocarbons, Brominated; Hydroxyl Radical; Lipid Metabolism; Lipid Peroxidation; Oxidation-Reduction; Pentanones; Phenols; Pulse Radiolysis; Spectrophotometry; Styrenes

The antioxidant properties of three related compounds, dehydrozingerone, isoeugenol and eugenol, were investigated using various models. Isoeugenol was found to be the most active in inhibiting ferrous-ion-, ferric-ion- and cumene-hydroperoxide-induced lipid peroxidation in rat brain homogenates. These compounds also showed significant hydroxyl radical scavenging activity. Isoeugenol was potent in scavenging superoxide anion generated by the xanthine-xanthine oxidase system, whereas eugenol was found to inhibit xanthine oxidase. The high antioxidant activity of isoeugenol may be due to the presence of a conjugated double bond, which increases the stability of the phenoxyl radical by electron delocalization. Such electron delocalization is not possible with eugenol. In dehydrozingerone, the stability was decreased by an electron withdrawing keto group at the para position.

Topics: Animals; Antioxidants; Drug Stability; Eugenol; Female; Free Radical Scavengers; Kinetics; Lipid Peroxidation; Male; Nitroblue Tetrazolium; Rats; Structure-Activity Relationship; Styrenes; Thiobarbituric Acid Reactive Substances