Synthesis Of C-Glycoside Analogues And Their Anti-ischemia And Anti-anoxia Evaluations

Cardiovascular and cerebrovascular diseases are great menace to people and coronary artery disease (CAD) is a typical cardiovascular and cerebrovascular diseases. The high prevalence of CAD is wide because of the aging of the population and other problems. CAD is not only a medical problem but also a social burden. It is estimated by World Health Organization that CAD will account for 5.9% of the total global disease burden and 11.2% of that in developed regions in 2020. The incidence and mortality of CAD in our country is increased very rapidly companying with our country economy's developing and the life style's changing. Medicinal treatment is still a cornerstone of CAD therapy, but many clinical drugs have showed side effects, drug resistance and other problem. So it is an urgent task for medicinal researchers to find effective and low toxicity drugs for CAD patients.The active ingredients of natural products are main sources from which people find medicine to heal illness. Salidroside is active ingredient of Chinese herbal drug Hongjingtian,which belongs to O-glycosides and have showed effective treatment for CAD. Salidroside have protective effects on myocardial cells following hypoxia/reoxygenation induced injury; however Salidroside metabolized very fast in vivo. Gastrodine is a neuroprotectant, which also belongs to O-glycosides and has similar drawback.In this study, we presented the basic pharmacophore against myocardial ischemia and anoxia from Salidroside and Gastrodine which served as lead compounds. The pharmacophore model includes glycosyl, substituted aryl and proper link chain between glycosyl and substituted aryl. In order to overcome O-glycosides'shortcomings of fast metabolism in vivo and to find novel effective anti-myocardial ischemic and anti-anoxic compounds, we designed three series of C-glycosides and one series of S-glycosides. We hope to indicate the C-glycosides'structure-activity relationships as an anti-myocardial ischemic and anti-anoxic pharmacophore. The results of primary biological activities evaluation indicated the presented pharmacophore had some reasonableness.The several parts of the present research works were summarized below:1. In this study, it was presented by us that glycosides'activities against myocardial ischemia and anoxia had close relationship about following two factors: the length of chain between glycosyl and substituted aryl and the substituted on aryl.2. Three series of C-glycosides and one series of S-glycosides were designed in order to resist the action of glycosidase and improve O-glycosides'chemical stableness. For the purpose of avoidance long carbon chain decrease the solubility of C-glycosides in water, one carbon atom in the middle of carbon chain was replaced by nitrogen. Three convenient synthetic routes were employed for the C-glycosides according to their structure, using Ramberg-B?cklund reaction, Wittig reaction and reductive amination reaction to synthesize the target molecules. 47 C-glycosidic compounds and 16 S-glycosidic compounds were synthesized and all of them are new compounds. The compounds were identified with 1HNMR and MS technique. 1D NOESY and 1H-1H COSY techniques were used to confirm the configuration of the glycosides, the results showed that the stereochemistry of the target molecules areβconfiguration.3. The target molecules were evaluated on the cellular model; a few of them were evaluated on animal model again. 59 compounds were evaluated on the hypoxia/reoxygenation injury model of cultured neonatal rat myocardial cells and glutamate induced damage model of SH-SY5Y cells. Lactic dehydrogenase (LDH) activity in medium of myocardial cells and SH-SY5Y cells were determined to evaluate target molecules'biological activities. 10 compounds have more protective effects than Salidroside on hypoxia/reoxygenation injury in cultured myocardial cells, 4 compounds have the similar protective effects to Salidroside. 10 compounds have more protective effects than Gastrodine on glutamate induced damage in SH-SY5Y cells, 5 compounds have the similar protective effects to Gastrodine. 2 compounds have showed protective effects on both two cellular models. 2 compounds were selected from 59 compounds to evaluate their anti-hypoxia activities on mouse. The results showed that these 2 compounds could prolong the living time of mouse under the normal pressure hypoxia obviously.4. Results of primary biological activities evaluation indicated that: (1) In protective effects on hypoxia/reoxygenation injury in cultured myocardial cells, the compounds that linked glycosyl and substituted aryl by -CH2NHCH2- chain had the best activities in all series of compounds. The compounds that linked glycosyl and substituted aryl by-CH2- chain almost hadn't activities. The compounds that linked glycosyl and substituted aryl by -CH₂CH₂- and -S-CH₂- chains had moderate activities. In the -CH₂NHCH₂- chain linked compounds, the compounds showed good activities when halogen atoms appeared in the aryl's o- or p- positions. (2) In protective effects on glutamate induced damage in SH-SY5Y cells, the compounds that linked glycosyl and substituted aryl by -CH2NHCH2- chain hadn't activities. Other compounds showed different activities on this model. (3) The compounds that have two carbon chain's interval between glycosyl and substituted aryl often showed activities on two above cellular models.