| Inflammatory bowel diseases(IBD), which include ulcerative colitis and Crohn's disease, are chronic inflammatory bowel diseases of unknown aetiology and have been popular among Europeans and Americans, now getting increased in Asian countries such as Japan, Korea, and China. Colorectal cancer is the fourth highest incidence of tumors in China, and the annual rising at a rate of five-percent. The UC is one of the important factors induce to colorectal cancer, in generally the possibility of malignant transformation of ulcerative colitis is three percent to five percent. Since 1930s to nowadays, sulfasalazine and 5-ASA as the main drugs were used to treat IBD. In recent years, studies have shown that 4-ASA in the treatment of IBD with 5-ASA have the same effect, only a certain difference in the role of the site and mechanism, and 4-ASA can be effective in the treatment of active and inactive ulcerative colon inflammation, and 4-ASA has fewer adverse reactions than 5-ASA. But after oral administrated significant amounts of free 4-ASA was rapidly absorbed in the upper gastrointestinal Road Department, only a little amount of free 4-ASA reaches to the colon lesions play a therapeutic effect. In the design of unsaturated fatty acid derivatives of 4-ASA, basing on the design principal of 5-ASA-glu and 5-ASA-asp, 4-ASA was connected with ligands which including undecylenic acid, sorbic acid andα-linolenic acid through the peptide bond. In this experiment, First unsaturated fatty acid generated anhydride and then combined with 4-ASA in order to enhance the reactivity of amino and yield. If theα-linolenic acid generated anhydride the first, it can improve the reaction activity, but can reduce the yield of product. In the synthesis of 4-ASA with linolenic acid, the carboxyl and phenolic hydroxyl of 4-ASA can combine with linolenic acid under the action of the DCC. Therefore,4-aminosalicylic acid (4-ASA) was protected by methoxyl, benzyloxycarbonyl and acetyl, respectively. The resultant was hydrogenised to remove protective group of amino group, and then was conjugated with linolenic acid to get the target product under the effect of phase transfer catalyst. The topics explored two synthesis routes about unsaturated fatty acid derivatives of 4-ASA.The structures of the new unsaturated fatty acid derivatives of 4-ASA were characterized by melting point, TLC, MS, FT-IR,1H-NMR and 13C-NMR spectra properties in details. On our study, we have provided a suitable synthesis route for further exploring new compounds in the treatment of IBD.Theory should develop and improve continuously under the practice and correction. Therefore, the new compound should be corrected the activity of an ideal anti-UC under the guidance of the parent of the new drugs and the new ligand. Pharmacodynamics of drug research is the most direct and accurate method to analysis and determine the activity of anti-UC.In this experiment we choose DNCB and acetic acid complex method to establish a mouse model of ulcerative colitis.Mice were randomly divided into normal control group(A), model group(B), 4-amino-acid azo derivatives of phenol group(C),4-ASA group(D). In addition to the normal control group(A), the rest were droped back with DNCB-acetone solution per day for 14 days. The 15th daily 0.1ml 0.3%DNCB-ethanol solution was poured into the colon. The 16th,0.2ml 3%acetic acid was poured into the mice with the same method.4-ASA group(D) in which the operation is the same as C group except 4-ASA instead of 4-amino-acid azo derivatives of phenol at 200 mg/kg/d, the normal group feed were given for each group in the experiment, the therapeutic effect was accessed by Disease activity index(DAI) and histological score. Compared with model group, the inflammatory symptoms and injuries of colonic mucosa were significantly alleviated in treat group(P<0.01). The azo derivatives of 4-aminosalicylic acid has a good effect on experimental ulcerative colitis, its mechanism of action must be research gradually. |
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