Studies On The Synthesis And Bioactivities Of Cinnamic Acid Derivatives

Natural products are one of the most important sources of the lead compounds in agrochemicals and drugs discovery. Derivatives of cinnamic acid, are widely distributed in plants have attracted considerable attention due to its various biological activities. Perfect effects has been showed on the prevention and treatment of several pathological injuries and diseases induced by oxidative stress and the inhibition of plant growth. To our knowledge, it represents a validated and yet promising target for drug discovery and definite interest for the purposes of creating new highly effective drugs based on it. For these reasons, our research interest is focus on the field of cinnamic acid derivatives as lead compound to design and synthesize its new analogues. In addition, we further investigate the antioxidation activity, antitumor activity, hepatoprotective activity against isoniazid-induced hepatotoxicity, inhibitory activity of plant growth and related mechanisms, their structural importance for these biological activities were also studied, the main results of the dissertation are outlined as followings:1. Two cinnamic acid amides of OA isolated from Garlic (Allium sativum. L) as lead compounds, we synthesized two series of cinnamic acid amides of OA and DA with various substituents respectively, and further investigaed the antioxidant and antityrosinase activities. The results indicated that most of the compounds showed significant antioxidant and antityrosinase activities, according to further SARs analysis, there was no evidence for direct correlation between free radical scavenging activity and tyrosinase inhibition, however, it interesting to find that with the same acid moiety, OA derivatives showed more inhibitory effect on tyrosinase than compounds derived from DA, whereas DA derivatives were found to have higher antioxidant activity than compounds derived from OA, the antioxidant and antityrosinase activities were considerably influenced by the position and number of the electron donating groups (-OH and -OMe) on the benzene rings and the presence of N-H group was in agreement with earlier findings, the relationship between their structures and their potencies demonstrated in the current study will be useful for the design of optimal agents. Based on the results for antioxidant design and in continuation of our ongoing research program in the field, we designed and synthesized four series of novel hydroxycinnamic acid derivatives with two N-H groups and various electron-donating group on the ring and analyzed their structural importance for the antioxidant activity. The results indicated that most of the compounds showed superior ability to scavenge radicals as the novel antioxidants.2. C. elegans was used as a model organism to its possible efficacy for anti-cancer effect, rapid preliminary acute toxicity and molecular mechanism of synthesized cinnamic acid amide derivatives. The results indicated that the calculated LD50 values of all the compounds were more than 20 mmol/L and suggested the toxicity of the compounds were lower, compound 3 b which has the highest antioxidant activity of the synthesized compounds did not significantly suppressed the Ras/MAPK pathway in Caenorhabditis, whereas,4a and 3a likely to be a potential anti-cancer drug candidate with high efficiency and low toxicity, the results indicated that there was no direct correlation between free radical scavenging activity and anti-cancer activity, it also indicated the molecular mechanism of action may not be caused by cytotoxicity to VPCs and might be mechanism-based. The transcription levels of related genes on the pathway were determined by quantitative real-time RT-PCR, results showed that the locations and interactions of the agents on Ras/MAPK were downstream of let-60/ras and upstream of mpkl/erk.3. A strategy using molecular hybridization approach was combining cinnamic acid antioxidants with antimycobacterial agents by an amide linkage to get bifunctional compounds with better antimycobacterial and hepatoprotective activities, the antimycobacterial activities of the 40 synthesized compounds were evaluated first and compound 3f demonstrated the most potent inhibitory activity (MIC=18.5μM). In the further study, compound 3f hydrolyzed to yield the two functional molecules (antioxidant and antimycobacterial) gradually by HPLC analysis, then the antioxidant molecule can exert its hepatoprotective activity as an inhibitor of free radical generation as well as through its role as a scavenger. Histopathological changes also indicated liver specimens obtained from animals treated with compound 3f did not show any histological changes. The expressions of hepatic genes CYP2E1 gene were determined by quantitative real-time RT-PCR, results showed that compound 3f may reduce free radical generation via inhibition of hepatic CYP2E1 and increase the removal of free radicals. This strategy was proved useful in design of antimycobacterial agents and for the future work in antimycobacterial research and treating of hepatotoxicity induced by oxidative stress. Overall, compound 3f was likely to be a potential antimycobacterial drug candidate with high efficiency and low toxicity, the work is still in progress.4. The cinnamic acid derivatives with attracting inhibited activity on the germination and growth of plants as our lead compounds, we synthesized three series derivatives with various substituents on the ring including fluorinated and chlorinated analogues, all the synthesized compounds were screened for their germination inhibition activity on radish(Raphanus sativus L.). The results indicated that most of the compounds showed significantly germination inhibition activity with high concentration, while with the low concentration, the activity became weaker. When the concentration was more than 100 ppm, it was observed that with the increase in concentration of the test solution, the activity also increased and in a dose-independent manner. SARs indicated that the effect of electron withdrawing group (F and Cl) on the benzene ring increased the activity and the alcohol-OH group has higher activity than phenol-OH group. Significant activity was exhibited by compound 9a, at 400 ppm concentration, there was only 10% of seed germinated which is at par with the standard, metribuzin. The mechanism study indicated that it belong to the photosystem inhibiting type herbicides, beyond that there were also a great influence on the contents of a-amylase activity.