Synthesis And Transdermal Anti-inflammatory Analgesic Activities Of Sinomenine Derivatives

Sinomenium acutum(Thunb.) Rehd.et Wils and S. acutum(Thunb.) Rehd. et Wils var. cinereum Rehd. et Wils. have been extensively used in China for the treat ment of rheumatoid arthritis.Sinomenine, which was isolated from the roots and stems of the plants, is an isoquinoline alkaloid that has been demonstrated as the active ingredient in the rheumatoid arthritis treatments. However, there are still some disadv antages for the application of sinomenine, such as poor transdermal permeation for external use, short half-life and large dose requirement. The worse is, when administered orally or by injection, cells would be stimulated to release excessive histamine, l eading to side effects like rash, leukopenia, anaphylactic shock and gastrointestinal reaction. Pharmaceutical preparation of Sinomenium was able to deliver the above-mentioned issues to some extent. However, the problems of side effects or short half-life were incapable of complete elimination. It is notably that drug efficacy could be proved significantly by the structural modification of the compounds. Thus, synthesis of novel derivatives from sinomenine for more effective Rh drugs has attracted increasing attention for decades in modern pharmaceutical research.In the first chapter, reviews on synthesis and pharmaceutical applications of the sinomenine derivatives were delivered based on the previous documentations. Then, on the basis of the previous research work from our laboratory, research objective of the dissertation has been put forward as follows: 1) three series of novel sinomenine derivatives were designed and synthesized; 2) then evaluation on transdermal permeation, analgesia and anti-inflammation activities of the synthesized sinomenine derivatives has been demonstrated.Successively, the second chapter focused on the synthesis of the novel sinomenine derivatives. On the basis of the theoretical knowledge of the pharmaceutical chemistry, such as the combination principle, polar theory, acetyl and aliphatic groups were introduced on the C1 and C4 positions of sinomenines successfully by the esterification or etherification protocols. And up to 16 different unprecedented sinomenine derivatives were smoothly afforded, including compounds 1 with two ester groups on the C1 and C4 positions; compounds 2 as 1-methoxy-4-alkoxy substituted sinomenine derivatives and compounds 3 with an ester group on C1 and an alkoxy group on C4 positions. The objective compounds were successfully synthesized from easily-accessible starting materials like paraformaldehyde(PFA), haloalkanes, carboxylic acid, carboxylic acid anhydride and so forth. Moreover, most reactions were conducted with assistance of 4-dimethylaminopyridine(DMAP), dicyclohexylcarbodiimide(DCC) and other common chemicals, feathering for easy operation and high efficiency. All the synthesized compounds were examined and confirmed by 1H NMR, 13 C NMR and MS, and the structure of compound 3f was analyzed by X-ray diffraction.Then, in chapter 3, HPLC analysis was selected as the optimal quantitative determinative method for the analysis of objective sinomenine derivatives in the dissertation, due to the superiority to UV analysis. While Kuming mouse was selected for transdermal permeation studies of the parent sinomenine and their derivatives. Transdermal permeation rates of the 16 new compounds was detected within 10 hours and compared with the parent compound. The results showed that the permeation rate of the parent compound reached its peak in 8 h, ca. 74.87% ± 2.08%. Surprisingly, the newly produced sinomenine derivatives showed higher transdermal permeation activity. For example, the transdermal permeation rate of the compound S1 a – S1 c reached their peaks in 2 h, ca. 98.05% ± 1.79%, 97.28% ± 1.59% and 87.28% ± 1.39%, respectively. While it took 6 h for Compound S2a- S2 e and S2 g to reach their transdermal permeation rate peaks, ca. 85.78% ± 2.21%, 85.36% ± 2.12%, 77.35% ± 2.48%, 82.05% ± 1.87%, 78.31% ± 1.78% and 72.75% ± 2.43%, respectively. The transdermal permeation rate of the compound S2 f reached its peak within 2 h after the penetration. But the decomposition of the compounds also was observed shorty after the peak rate. While the decompositions of the parent sinomenine and other derivatives were observed in ca. 8 h after the penetration. By comparison, permeation rates of the compounds S3 a – S3 f reached their peaks in 4 h, approx. 85.48% ± 3.23%, 85.78% ± 1.46%, 86.25% ± 3.52%, 85.58% ± 2.63%, 85.88% ± 2.46% and 86.75% ± 3.02%, separately. Compared with the parent sinomenine, the synthesized derivatives in the dissertation afforded significantly improved transdermal permeation activity as concluded from the results of statistic calculations(p < 0.05).In Chapter 4, the anti-inflammatory and analgesic effects of these derivatives were also evaluated by a series of experiments, including lipopolysaccharide-induced inflammatory factor(IL1?, IL6, TNF-?(8) expression in Raw 264.7 cells, the hot plate test and the acetic acid-induced writhing test, dimethylbenzene-induced ear oedema in mice, carrageenan--induced paw oedema in rats. The results demonstrated that compounds S1 and compounds S3 exhibited stronger anti-inflammatory activities but similar analgesic effects in comparison with the parent compound. Findings that demonstrated in the dissertation are of great significance as the directive guidance for the modifications on the sinomenine derivatives and explorations for novel, more effective sinomenine derivative of greater potentials.