Study On Design And Synthesis Of Derivatives Of Rosmarinic Acid And Their Inhibitory Activities Against Matrix Metalloproteinase 1

Matrix metalloproteinase 1 (MMP-1) is an important member of Matrix metalloproteinase family,plays a pivotal role in degradation of interstitial collagen types I,II,III,VII,X and XI,and undergoes remodelling and degradation during vital physiological processes such as angiogenesis,wound healing,and development.Hence,looking for MMP-1 inhibitors with high activity is significant to the development of new medicines targeted at arthritis,cancer and so on.In this thesis,the following work had been carried out:1. The paper firstly summarized the general research situation of Rosmarinic acid and its derivatives,MMP-1 and its inhibitors.The structure characteristics of MMP-1 inhibitors were also summarized.2. According to the structural features of MMP-1 inhibitors,a series of potential compounds were designed and synthetized by combining the screened results of natural products with the method of computer aided drug design.3. The total synthesis of (±)-Rosmarinic acid and its derivatives were studied,as well as effects of different reaction conditions on different reactions.An efficient synthetic route of (±)-Rosmarinic acid and its derivatives with high yield was obtained.4. The activities of the MMP-1 inhibitors were evaluated by using FRET method. It was found that the compounds,such as ln,2n,and 2j,exhibited excellent activity of inhibiting MMP-1 with an IC50 value of 2.5μM,4.2μM,and 3.6μM,respectively.5. The relationship between the structures and activities of the compounds were investigated and the results showed that the activity of inhibiting MMP-1 could be enhanced by using group R1 as hydrophilic group, R2 as the greater electronegativity group with a high capability of chelating Zn2+ and R3 as a large hydrophobic group.The research will be beneficial to the design of more MMP-1 inhibitors with higher avtivities.