Resveratrol (3,4Ј,5-trihydroxystilbene) is a phytoalexin found in grapes and certain other plants. In recent years, there have been a large of reports about resveratrol and it exhibits a variety of useful bioactivities including anti-inflammatory, cancer chempreventive, antiplatelet aggregation, antioxidative and antibacterial activities. [1][2][3][4] In past years, resveratrol and some its analogs were synthesized. [5][6][7][8] This intrigued us to prepare its analoges and their derivatives and investigate their bioactivities. In order to increase its stability and water-solubility, we designed and synthesized some analogues of resveratrol by substituting one of two benzenes with pyridyl and their Mannich base and phenoxy acetic acid derivatives of phenol, and tested their anti-inflammatory activity in mice in order to find new potent anti-inflammatory agents. Results and DiscussionResveratrol and its analogues were synthesized according to Chart 1. Starting from 3,5-dihydroxybenzoic acid or 4-hydroxybenzoic acid, the compounds 2a, b were prepared in good yield, followed by reduction with LiAlH 4 . Subsequent treatment of 3a, b with SOCl 2 afforded 4a, b in about 94%. Using Wittig-Horner reaction, the compounds 5a, b were obtained by refluxing 4a, b with P(OEt) 3 , which were condensed with ArCHO in NaOEt/DMF to give 6a-f, only the trans isomer was obtained. BBr 3 was used for deprotection of methyl groups in CH 2 Cl 2 to afforded 7a-f.The derivatives were prepared according to Scheme I or II. The ethyl aryloxyacetates 8a-f were synthesized by the reaction of compounds 7a-f with ethyl chloroacetate in the presence of KOH in ethanol-DMF and hydrolyzed to afford aryloxyacetic acids 9a-e. Some Mannich base derivatives were prepared by the Mannich reaction of compounds 7 with morpholine and 36% HCHO in boiling ethanol or 1,4-dioxane (Scheme II).The structures and physical data of these new compounds were listed in Table 1.Ten target compounds, three intermediates and resveratrol with ibuprofen were tested for anti-inflammatory activity at doses of 200 mg/kg body weight by xylene-induced ear-edemaic mice according to the method described by Xu Shuyun.9) The results were summarized in Table 2. At the tested doses, resveratrol was the most active compounds inhibiting the edematous response by 38.9%. Target compound 9c showed almost the same inhibition rate as resveratrol by 37.0%. The other compounds (9d, 11b, 12c) showed an edema reduction ranging from 30 to 35%. As expected, the reference NSAID Ibuprofen provoked 42.2% edema reduction. The pharmacological tests showed that resveratrol pyridyl-substituted analogs and the Mannich base have potent anti-inflammatory activity. ExperimentalGeneral Except where indicated, materials and reagents were used as supplied by the manufacturer. Melting points were determined with Yanaco micro melting point apparatus and were not corrected. NMR spectra were recorded at 300 MHz using Bruker ARX-300 instrument with TMS as internal reference. Mass spectra (ESI-MS) were measured on Agi...
Depression is a common illness associated with high rates of chronicity, relapse, and recurrence; psychosocial and physical impairment; and a high suicide rate. Nonetheless, many currently available antidepressants have low rates of response and remission. Moreover, contemporary antidepressants can produce many unwanted side effects. 1) Therefore, research for new antidepressants with greater effectiveness without any (or with lower) adverse effects is still desirable.In Oriental society, herbs and herbal preparations have been widely used as medicines by consumers for many centuries. Some of the herbal medicines may be effective alternatives in the treatment of neuropsychiatric diseases such as depression. Anemarrhena asphodeloides BUNGE (Liliaceae) is commonly found in traditional Chinese herbal medicines, and has been shown to have antidepressant effects in mouse models of behavioral despair tests.2) Sarsasapogenin, 5b,20a,22a,25S-spirostan-3b-ol, is a major active component of Anemarrhena asphodeloides, which exhibits a variety of pharmacological effects such as the promotion of neurogenesis activity, antioxidative action and improving cognitive impairment [3][4][5] ; however, no information is available about its antidepressant activity. In the present study, we assessed the potential antidepressant effects of sarsasapogenin from Anemarrhena asphodeloides by means of behavioral, pharmacological and neurochemical procedures. MATERIALS AND METHODS MaterialsSarsasapogenin with a purity of 98% was obtained as described in a previous study.5) In short, the method involved acid hydrolysis, extraction with organic solvent and repeated recrystallization.Animals Male Swiss mice, weighing 20-24 g, were used throughout the study. The animals were supplied by the Experimental Animal Centre of Shenyang Pharmaceutical University. Mice were maintained under standard housing conditions in a 12L : 12D light/dark cycle (light on 6:30) with free access to water and standard food. Dose and Route of Administration All drugs were suspended in 0.5% CMC-Na. Sarsasapogenin in doses of 12.5, 25 or 50 mg/kg and fluoxetine hydrochloride in a dose of 20 mg/kg were administered orally once daily for 14 d. A control group of animals received 0.5% CMC-Na only. The behavioral tests and the neurochemical assay were performed 1 h after the last administration on the 14th day.Forced Swimming Test The forced swimming test (FST) was similar to that described by Porsolt et al. 6) Briefly, mice were individually placed in a glass-polycarbonate cylinder (height: 25 cm; diameter: 10 cm) filled to a depth of 10 cm with water maintained at 24°C and were allowed to swim for 6 min, and the durations of immobility were recorded during the last 4 min of the test. Open-Field TestThe open-field apparatus was a field, 80 cm in diameter, which was demarcated into 36 approximately equal areas. The animals were placed individually in the center of the arena and allowed to explore freely. The number of times the animal crossed squares was recorded for 3 min.D...
Despite cancer chemotherapy has entered a new era of molecularly targeted therapeutics and some forms of cancer have been successfully treated by modern therapies, the successful treatment of cancer remains a significant challenge in the future because chemotherapy is limited by the drug resistance and adverse side effects.1) In order to develop more effective and reliable anticancer agents that circumvent these limitations, the search for novel anti-tumor agents has turned to natural products, in particular plants used in traditional folk medicines. 2)In recent years, artemisinin and its derivatives have been widely studied for their anticancer activities. Some of them showed excellent anti-tumor activity toward different cancer cell lines in vitro. [3][4][5][6][7][8][9] Also, several studies demonstrated that artemisinin analogues were effective to many drug-and radiation-resistant cancer cell lines due to their multiple mechanisms. 10,11) The main mode likely involves a similar metalinduced free-radical formation leading to induce apoptosis in cancer cells and inhibit the tumor angiogenesis. [12][13][14][15][16] Recently, considerable attention has been focused on chalcones, which are a class of privileged structures that are easily prepared and have a wide range of biological properties, [17][18][19][20][21] which makes them an attractive pharmacophoric scaffold. An area of particular interest is their potential as antitumor agents, for which several modes of action have been proposed. The key mechanism is the inhibition of tubulin polymerization, while also including the inhibition of angiogenesis and the induction of apoptosis. [22][23][24] Chalcones and artemisinin analogues represent two classes of natural products, whose antitumor effects appear to be consistent via different molecular mechanisms. As the application of hybrid strategy to synthesize artemisinin analogues are continuously emerging, 9,25) it is reasonable to combine their structure analogues to form a single molecular framework with a linker, which would allow us to find more potent anti-tumor agents, in which these 'merge' pharmacophore may be addressing the active site of different targets and offering the possibility to overcome drug resistance. Intrigued by these observations, we designed and synthesized two new series of novel artemisinin derivatives by replacement of oxygen at C-10 with nitrogen, in which the substituted chalcone group is bonded to the artemisinin nucleus through an oxyacetyl linkage.Chemistry The synthetic routes of compounds are outlined in Chart 1. Separable diastereomeric mixture of 10b-azidodihydroartemisinin (2) and 10a-azidodihydroartemisinin (3) were obtained by treating 1 with trimethylsilyl chloride, sodium azide and sodium iodide at room temperature for 28 h, according to ref 6. The a and b isomers appeared as two distinct spots on TLC and were separated by column chromatography, with b-isomers as the major products. The reduction of azido compounds (2, 3) with Staudinger reaction afforded the correspondin...
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