Design And Synthesis And Activitics Of Chalcone Compounds

OBJECTIVE:Chalcones characterized with the backbone structure of 1, 3-diphenylpropenone have extensive biological activities, and they are also the effective components of herb plants. Base on a good deal of relevant documents at home and abroad, this dissertation try to design and synthesize new chalcones with specific structure, in which their bioactivity were evaluated. Using the technology of computer aided drug design, the structures of compounds were optimized to the minimum energy and conducted with conformational analysis in SGI RZ4000 graphic station. Structure-activity relationship of chalcones compound were studied and perfected, in order to get lead compounds with antitumor and anti-inflammatory activities. In addition, these work can provide valuable message for new drug design and development.METHODS:On the base of the survey of a good deal of relevant documents at home and abroad, our work follows the general procedure for new drug development. Firstly, we studied the documents at home and abroad about the structure-activity relationship of antitumor chalcones and anti-inflammatory chalcones, as well as the classical structure-activity relationship of third generation aromatic retinoid. We design and synthesize new chalcones with specific structure, and evaluated the pharmacological activity of target comounds, in which majoring in their antitumor activity and anti-inflammatory activity. Antitumor active screening experiment focus on the reversion of the inhibition induced by TPA, while as anti-inflammatory active screening experiment focus on the evaluation of the antagonist induced by LTD4 and the inhibition rate induced by PLA2. Secondly, combine the result of pharmacological activity screening, low energy comformations of all target comounds were obtained by means of energy minimization of molecular structures using SYBYL7.3 software package provided by co. Tripos in Silicon Graphics IRIS Indigo RZ4000 graphic station. Divinable CoMFA models, namely 3D-QSAR of antitumor chalcones, were studied according to the calculated structural parameters. These results obtained would be useful for further research such as the synthesis of new compound and their bioactivity forcast. RESULTS:We substitute the A ring (or B ring) of chalcones with hydrophbic t-butyl group which has greater steric hindrance. Changing the substituent of B ring (or A ring) and conjugate structure between the two ring, twenty-four new chalcones have been designed and synthesized for the first time and their structures were determined by mass spectrum and elemental analyses. Eighteen compounds have been tested for antitumorigenic activity and all of the experimental compounds possess antitumorigenic activity. Inside of them, four compound possess preferable activity and two compound could be developed to antitumor lead compound. The bioassays for anti-inflammatory activity of fourteen compounds were carried out. The antagonist induced by LTD4 and the inhibition rate induced by PLA2 of four compounds reach to above 20%, inside which two compounds reach to above 30% which will be candidate of anti-inflammatory lead compound. Low energy comformations of all target comounds were obtained by means of energy minimization of molecular structures using SYBYL7.3 software package provided by co. Tripos.3D-QS AR of antitumorigenic chalcones were established according to the calculated structural parameters, and the structure-activity relationship have also been discussed.CONCLUSION:Through the synthesis, screening, energy optimization and conformation analysis, we establish CoMFA model, namely 3D-QSAR of antitumor chalcones, in Silicon Graphics IRIS Indigo RZ4000 graphic station. The results show that:(1) the experiment explored preliminarily the approach of exploiting new lead compound in de novo Drug Design, which include computer aided design, organic synthesis and bioactivity assay; (2) further discuss the structure-activity relationship of antitumor chalcones; (3) reveal the foreground of synthesize structure-modified chalcones and finding new chalcones with antitumor and anti-inflammatory activities.