| Chinese traditional medicine citrus is the dried fruit skin of rutaceae plants orange (Citrus reticulata Blanco) and its cultivar, only contained the "Shen Nong’s Herbal Classic", as the product, its spicy, bitter and warm taste, with regulating qi-flowing for strengthening spleen, drying dampness and resolving phlegm, taken orally to spleen and stomach and qi stagnation syndrome, vomiting, hiccups, wet phlegm and cold cough, sputum obstruction, etc. Its main origins were Guangdong, fujian, sichuan, zhejiang, jiangxi and other places. Late early winter when the fruits were ripening, harvested its ripe fruit peel and dried or dried at low temperature. As the long storage time is preferred, therefore calls the dried tangerine or orange peel. We call "Xinhui" peel or madarin orange peel which originating in Guangdong Xinhui. Hesperitin (hesperetin), is the main therapeutic effects of rutaceae plants of the genus citrus fruit dried tangerine or orange peel, have anti-inflammatory, antioxidant, antibacterial, anti-cancer, immunity adjustment, radiation protection, protecting cardiovascular system, such as pharmacological activities, increasingly cause the extensive concern of the botanist and pharmacologist.Our previous research have found that 5,7,3’-triacetyl hesperetin suppressed adjuvant-induced arthritis in rats through modulating JAK2/STAT3 pathway. And 7, 3’-dimethoxy hesperetin inhibits inflammation by inducing synovial apoptosis in rats with adjuvant-induced arthritis. Recently, the interactions between the Notch signalling pathway and angiogenesis have been described in RA. And Jong-Sung Park found inhibition of Notch signalling can ameliorate experimental inflammatory arthritis. Thus we guess if hesperetin has effects on Notch signaling. But hesperetin’s poor solubility in water and low bioavailability which only work in large doses limits its further application. Therefore, in order to have better resource development and utilization of new drugs, it is necessary to carry out modification of hesperetin structure, looking for good water solubility, higher activity hesperitin derivatives. According to review the related literatures, we found Mannich bases have been associated with increased bioactivity and solubility. The presence of a Mannich base group in many natural products may increase biological potency due to the greater number of molecular sites for electrophilic attack by cellular constituents, as well as due to the cascade effect of preferential chemosensitization.However, its low bioavailability (< 25%) and its poor solubility in water which only work in large doses limits its further application. Therefore, in order to have better resource development and utilization of new drugs, it is necessary to carry out structure of hesperitin structure modification, looking for good water solubility, higher activity hesperidin derivatives.Specific research work includes the following four parts:1. The synthesis of hesperitin derivatives, by reviewing the literatures, we found the Mannich reaction can be introduced in 6’ place of hesperitin an amine methyl, the mothed was using hesperitin as the raw material, by condensation with formaldehyde and primary amine or secondary amine, generates beta amino carbonyl compounds, amino (carbonyl compounds called product beta "Mannich bases" (Mannich bases), herein after referred to as man.2. Determination of water-solublity:using ultraviolet spectrophotometric method determinate the water-soluble of these compounds, found that hesperitin derivatives were better than matrix.3. Anti-inflammatory activity screening:select mice abdominal cavity macrophage RAW 264.7 cell lines to screen the anti-inflammatory activity of hesperitin on mann’s base, set up the normal group, the LPS stimulation group, and the drug group (including hesperitin and mannich bases alkali), ELISA kit to detect the contents of TNF alpha and IL-6, found that compounds 3c,3e,3i have obvious anti-inflammatory activity.4. Related protein expression and possible mechanism. |
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