Aldose Reductase Inhibitors Screening And Curcumin Analogues Anticancer Activity3D-QSAR Research

Aldose Reductase (AR or ALR2) is the key enzyme in the polyol pathway that play a key role in the diabetes complications, which also has been confirmed relate to the inflammatory signals mediation. For the aldose reductase is closed to its homologous enzyme aldehyde reductase, previous Aldose Reductase inhibitors (ARIs) lack of the highly specifically selective to ALR2, which made the ARIs had serious side effects and unsatisfactory clinical results. This thesis mainly involes the screening of ARIs from natural product database, anti-inflammatory drugs database and curcumin analogues, which contained the focus on the anti-inflammatory effect of curcumin analogues. We also used the three dimensional quantitative structure-actiity relationship (3D-QSAR) to study the curcumin analogues antitumor cells based the previously research.We used of the molecular docking tools to virtual screening of the ARIs based on the natural product database contained over forty thousand natural products and the anti-inflammatory drugs database. To obtain the highly specifically selective ARIs, we used the screening compounds to run the molecule docking to ALR1protein. During the screening process, total127compounds’scores higher than7.5points, its structure-actiity relationship have been discussed and its selective inhibition have been screening, which could help the development of novel natural ARIs. In the anti-inflammatory drugs virtual screening, two potential non-steroidal anti-inflammatory drugs have been found, and one drug was similar to the serie ARI structures has reported.In the AR inhibition assay of curcumin analogues which used the gene engineering expression ALR2, A2showed the strong activity against ALR2, and A2also performance well in the anti-inflammatory experiments. In the Macrophages MTT assay, A2in5μM has reach half inhibition rate, and had statistic significant difference. In the TPA induced mouse ear edema and mouse skin model, A2could effectively reduce the inflammation, which was confirmed by the mouse ears organization fluorescence slice observation and ear hole weight has significant difference. In the IL-1β ELISA assay, A2could reduce IL-1β to25%at5μM. In addition, we established the3D-QSAR model based on the Panc-1, HT-29tumor cell MTT data by CoMFA method, its q2was0.580and0.722respectively. Used this model successfully predicted a novel serie of curcumin analogues, and S14, S31, S22exhibited the very good anti-cancer activity against tumor cell.