Chemical modification was performed for improving the antioxidant activity of lead compound glycyrrhetinic acid (Ib). Two conjugated diene derivatives were prepared by reduction and dehydration reactions. Their in vitro antioxidant activities were studied using a cytochrome P450/NADPH reductase system from rat liver microsomes. The generation of microsomal free radicals was followed by oxidation of the DCFH-DA probe, while evaluating the capacity to inhibit reactive oxygen species (ROS) formation. The initial result showed that the two homo- and heterocyclic diene derivatives--18beta-olean-11,13(18)-diene-3beta, 30-diol (IV) and 18beta-olean-9 (11), 12-diene-3beta, 30-diol (V) exhibited strong antioxidant activities, at a concentration of 1.0 mg x mL(-1), they inhibited free radical (ROS) formation by 45% and 41%, respectively. In the same conditions, the lead compound (Ib) and the reference vitamin E inhibited ROS activity by 31% and 32%. Our results suggest that the elimination of the 11-keto group and the chemical reduction of 30-carboxylic group into hydroxyl function can increase the antioxidant activity of Ib significantly.
Animals ; Antioxidants ; chemical synthesis ; pharmacology ; Glycyrrhetinic Acid ; analogs & derivatives ; Male ; Microsomes, Liver ; metabolism ; Rats ; Reactive Oxygen Species ; metabolism ; Triterpenes ; chemical synthesis ; pharmacology

AIMTo synthesize four water-soluble metal porphyrins [5, 10, 15, 20-tetra[4-(4'-pyridine-1) butyloxy phenyl] metalloporphyrins bromide, metal = Zn (I), Cu (II), Mn (III) and Co (IV)] as analogous enzyme having two anti-active oxygen functions.

METHODSThe first function, scavenging O2-, has been proved by using riboflavine-methionine photoreduction methods. The second function, scavenging H2O2, has been demonstrated by using the oxidating Vit C. The third function, scavenging HO*, has been demonstrated by using Fenton reaction. The complexes were measured by the mice liver homogenate technique of mice.

RESULTSFour model compounds could scavenge O2- in the concentration range of 1.0 x 10(-5) - 1.0 x 10(-6) mol x L(-1), decompose H2O2 in the concentration of 1.5 x 10(-6) - 1.0 x 10(-6) mol x L(-1), scavenge HO* in the concentration of 2.0 x 10(-8) - 1.0 x 10(-8) mol x L(-1). All showed that they had obvious action of decreasing the lipid peroxidation in the concentration of 1.0 x 10(-7) mol x L(-1).

CONCLUSIONAll above-mentioned complexes were considered to be qualified analogous enzymes of anti-active oxygen.

Animals ; Cobalt ; Copper ; Free Radical Scavengers ; chemical synthesis ; pharmacology ; Hydrogen Peroxide ; metabolism ; Hydroxyl Radical ; metabolism ; In Vitro Techniques ; Lipid Peroxidation ; drug effects ; Liver ; metabolism ; Malondialdehyde ; metabolism ; Manganese ; Metalloporphyrins ; chemical synthesis ; pharmacology ; Mice ; Reactive Oxygen Species ; metabolism ; Zinc

Doxorubicin (DOX) is one of the most potent anticancer drugs and induces acute cardiac arrhythmias and chronic cumulative cardiomyopathy. Though DOX-induced cardiotoxicity is known to be caused mainly by ROS generation, a disturbance of Ca2+ homeostasis is also implicated one of the cardiotoxic mechanisms. In this study, a molecular basis of DOX-induced modulation of intracellular Ca2+ concentration ([Ca2+]i) was investigated. Treatment of adult rat cardiomyocytes with DOX increased [Ca2+]i irrespectively of extracellular Ca2+, indicating DOX-mediated Ca2+ release from intracellular Ca2+ stores. The DOX-induced Ca2+ increase was slowly processed and sustained. The Ca2+ increase was inhibited by pretreatment with a sarcoplasmic reticulum (SR) Ca2+ channel blocker, ryanodine or dantrolene, and an antioxidant, alpha-lipoic acid or alpha-tocopherol. DOX-induced ROS generation was observed immediately after DOX treatment and increased in a time-dependent manner. The ROS production was significantly reduced by the pretreatment of the SR Ca2+ channel blockers and the antioxidants. Moreover, DOX-mediated activation of caspase-3 was significantly inhibited by the Ca2+ channel blockers and a-lipoic acid but not a-tocopherol. In addition, cotreatment of ryanodine with alpha-lipoic acid resulted in further inhibition of the casapse-3 activity. These results demonstrate that DOX-mediated ROS opens ryanodine receptor, resulting in an increase in [Ca2+]i and that the increased [Ca2+]i induces ROS production. These observations also suggest that DOX/ROS-induced increase of [Ca2+]i plays a critical role in damage of cardiomyocytes.
Sarcoplasmic Reticulum/drug effects ; Ryanodine Receptor Calcium Release Channel/metabolism ; Reactive Oxygen Species/*chemical synthesis ; Rats, Sprague-Dawley ; Rats ; Myocytes, Cardiac/*drug effects ; Male ; Female ; Enzyme Activation/drug effects ; Doxorubicin/*pharmacology ; Cells, Cultured ; Caspase 3/metabolism ; Calcium Channel Blockers/pharmacology ; Calcium/*metabolism ; Antioxidants/pharmacology ; Antibiotics, Antineoplastic/pharmacology ; Animals