| Chapter I Study the antioxidant properties of novel silybin and dihydroflavonol derivativesThe reduction of molecular oxygen leads to the formation of reactive oxygen species (ROS) including superoxide anion radicals (·O2-) and hydroxyl (OH·) radicals. Generally, the ROS has some physiological function such as bacterial ingestion. However, when the imbalance between cellular production of free radicals and the ability of cells to defend against them occurs, the ROS cause oxidative damage to cell components, and may play an important role in various pathological conditions. This damage may contritute to a variety of diseases in nervous system, such as stroke (a disease in acute central nervous system injury), Parkinson's disease and Alzheimer's disease (AD). It also results in other pathological processes, including cardiac disease, atherosclerosis, hypertension, autoimmune rheumatic disease, cancer, viral disease (such as AIDS) and aging. ROS, as the signal of message transduction intra-cellular, it also can activate nuclear factorκB (NF-κB), which binds to the promoter, related to inflammation and immunity, and increases the genetic transcription in nuclear. The occurrence and development of many diseases, such as actue, chronic inflammation, and immune imbalance and so on, may be attributed to this molecular biology base. Therefore there is considerable interest in the discovery and development of efficient synthetic or natural antioxidants to protect and therapy various diseases related to free radicals.Flavonolignan is a kind of flavones, which is coupled by catechol flavones and phenylpropanoids. The representative compounds of flavonolignans are silybin, isosilybin, silichristin, silidianin and 2,3-dehydrosilybin, which were isolated from silymarin. A lot of researches indicated that flavonolignans have many bioactivies such as antioxidant, hepatoprotective, anti-tumor, anti-inflammation, anti-cardiovascular diseases, anti-diabetes and anti-renal toxicity from medicinal resource. Flavonolignan, as a kind of lead compounds, possessing several of bioactivities, attracts many researchers to study their structure-activity relationship (SAR) and to develop new derivatives.Dihydroflavonols, belonging to flavonoids, in which 2,3-position is a single bond and 3-position is substituted by hydroxyl, are an important class of secondary plant metabolites. Many dihydroflavonols such as taxifolin, astilbin, ampelopsin show excellent activities. Dihydroflavonols exhibit a wide spectrum of pharmacological properties, including antioxidative, hepato-protective, antineoplastic, anti-virus, anti-inflammation, anti-fungi, anti-hypertension, and anti-hyperlipemia activities.The present study would be benefit for understanding the mechanisms of antioxidative activity of flavonolignans, such as silybin derivatives and dihydroflavonols and further optimize their application.Subject: We elucidate the antioxidant properties of these new derivatives of flavonolignans and dihydroflavonols and determine their structure-activity relationship as atitioxidants by using various experimental models. And this may be contributed to discover and develop new antioxidants.Methods: We established inhibition of xanthine oxidase, scavenging free radicals, protection of PC12 cells-insulted by H2O2 and inhibition of lipid peroxidation models to assay the antioxidant properties of new derivatives of flavonolignans and dihydroflavonols from different levels, and to determine their SARs.Results: Compound 2, one of silybin derivatives, demonstrated excellent antioxidant effect on scavenging superoxide anion free radicals, the IC50 of which was 2.65×10-5 mol/L, while the IC50 of quercetin (referfence compound) was 3.81×10-5 mol/L. Compounds 11, 12, 13, 16, 21 showed activities of scavenging·O2-, and IC50 values were 33.7±0.87, 18.78±0.84, 35.2±1.12, 30.05±0.65 and 36.32±1.55μg/mL, respectively, a little weaker than control (IC50=11.6±0.55μg/mL). Compounds 9-13, 21 exhibited anti-DPPH radicals activity, the values of IC50 were 11.73±0.46, 32.82±1.21, 6.64±0.72, 13.50±0.75 and 15.50±0.56, 2.65±0.45μg/mL, respectively, while the IC50 of control was 1.58±0.46μg/mL. Compounds 10, 11, 13, 21 had excellent effect of inhibition of lipid peroxidation. IC50 values were 20.52±0.65, 11.55±0.82, 3.52±0.25, 18.74±0.47μg/mL, respectively, and the IC50 of control was 8.63±0.53μg/mL. Compound 21 could markedly protect PC12 cells, insulted by H2O2.Conclusion: All of the data presented here demonstrated that compound 21 has antioxidant properties of scavenging superoxide anion and DPPH free radicals, protecting PC12 from injuring by H2O2 and inhibiting lipid peroxidation. Therefore, it is valuable to further study this compound. Compounds11, 12, 13, 16, 21 can scavenging superoxide anion, compounds 9-13, and 21 can capture DPPH radicals and compounds 10, 11, 13,21 can blocking chain reaction by inhibiting lipid peroxidation. Periplaneta americana is widely distributed in China. Although it was well known as an active carrier of pathogenic organisms, as well as for damaging stored products and being aesthetically unappealing and offensive . It was employed as folk medicines for the treatment of toxic disorders and Children's malnutrition since ancient China. The earliest record could be found in 'ShenNong Bencao Pharmacy', which was more than two thousands years ago. In this study, the anti-tumor effects of extracts from Periplaneta americana was evaluated with both in vitro and in vivo models.Subject: To evaluate the anti-tumor activities of Periplaneta Americana extracts.Methods: To evaluate the cytotocicities of Periplaneta Americana extracts, such as the human nasopharyngeal carcinoma CNE,carcinoma cervicis Hela,human chronic granulocytic leukemia K562,prostatic carcinoma PC3,gmouse macrophae P388 D1 in vitro and to evaluate the anti-tumor effectivities in vivo by transplanted mouse sarcoma S180 model.Results: In vitro, about 50 in 147 samples more or less inhibited the proliferation of CNE, Hela, P388 D1, K562 and PC3 cell lines, and a few of samples, such as RL-A0711-(17-20) significantly inhibited the proliferation of K562, with the IC50 value < 10μg/mL. In vivo, SLY-1 sample of low dose (500 mg/kg) and SLY-1 of high dose (1500 mg/kg) both inhibited the growth of S180 cell, the inhibitive rate were 36.23% and 50.72%, and the spleen index were 6.84 and 5.74, the thymus index were 1.93 and 2.25. Only SLY-2 sample of high dose (1500 mg/kg) inhibited the growth of S180 cell, the inhibitive rate were 39.13%, and the spleen index were 6.84, the thymus index were 2.13.Conclusion: These results indicated that PAE possesses potent anti-tumor activity on the models that we have employed. Its anti-tumor mechanism are probably associated with the enhancing of immunity. |
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