| The paper consists of two parts:Part 1:Synthesis, bioactivities and structure-activity-relationships (SAR) of stilbene derivatives.The stilbene extracts of Cajanus cajan L. mainly consists of Cajanine, longistyline A and longistyline C, which belong to the family of diphenylethene. They are good lead compounds because of a variety of bioactivities, such as anti-osteoporotic activity, antihyperlipidemic activity, hypoglycemic effect, anti-inflammatory analgesic activity and anti-tumor activity. However, there are no reports on the total synthesis and SAR research of those compounds and their derivatives up to now.Cajanine, longistyline A and longistyline C were synthesized for the first time in this paper, and two synthesis routes for the cajanine were accomplished, which were applied to synthesize different type of derivatives. Six synthesis routes were accomplished in this part, and 105 compounds (76 compounds are novel) were synthesized,49 (45 compounds were novel) of which were target compounds. Additionally, target compounds were evaluated for their antiviral activity, neuroprotective effect and anti-cancer activity in vitro. The results of antiviral activity in vitro showed that compounds 1,5c,6c,6d,8,8c,8d,9,11d,12c,12d,13c,13d, 18a,19,25,26,29,37 and 38 presented potent activity against influenza virus A, of which the IC50 value of compounds 6c (0.21μg/ml),6d (0.48μg/ml),8 (0.48μg/ml),9 (0.27μg/ml),12d (0.36μg/ml),29 (0.21μg/ml) and 37 (0.48μg/ml) was even lower than that of positive control RBV (0.96μg/ml) and Tamiflu (0.66μg/ml). Consequently, those compounds deserve further research and development. Compounds 1,5d,6d,9, 10c,10d,13c,13d,26,32,33 and 38 also showed potent activity against COX B3 virus, of which the IC50 value of compounds 1 (0.73μg/ml),9 (0.65μg/ml),6d (0.29μg/ml),10c (0.86μg/ml), 10d (0.48μg/ml),15d (0.50μg/ml),33 (0.73μg/ml),38 (0.32μg/ml) was relatively low, and far lower than that of RBV (292.46μg/ml). Among the compounds tested,1,3c,3d,8,9 and 26 exhibited potent activity against COX B6 virus, among which the activity of compounds 1 (0.90μg/ml) and 9 (0.69μg/ml) was much stronger. The preliminary SAR research showed that hydrogen or methoxycarbonyl substitute on the 1 position of benzene ring A, insertion of two metylenes between benzene ring B and double bond, and methyl substitute on the 3' position of benzene ring B favor the activity against influenza virus A. Hydrogen or carboxyl substitute on the 1 position of benzene ring A benefits the activity against both COX B3 and COX B6. Methyl substitute on the 3'position of benzene ring B also favor the anti COX B3 virus activity.The neuroprotective effect of target compounds was assayed in the model of serum-deprived injury in PC 12 cells. The result showed that compounds 2c,4c,8,13c and 18 show some neuroprotective effect. The number of survival cells (75.1±3.6, 82.0±3.2,76.6±5.8,84.7±5.0,77.8±6.3) was obviously higher than that of model (69.3±4.1). The SAR research showed that methoxycarbonyl substitute on the 1 positon of benzene ring A, insertion of conjugated double bond between benzene ring A and B, and hydrogen bond receptors substitutes on the 2'position of benzene ring B favor neuroprotective effect.Additionally, the antiproliferative activity of target compounds was test in the A549, HepG2 and T47D cells using the standard MTT assay. The results showed that only longistyline A and C presented some antiproliferative activity (inhibition ratio: 34.51%,48.11%,12.01% for longistyline A, and 25.22%,40.88%,15.64% for longistyline C), and other compounds did not show obvious antiproliferative activity.Part 2:Synthesis, antiviral activities and SAR of glutarimide derivatives.On the basis of previous work, we constitute to investigate the synthesis and antiviral activities of glutarimide derivatives, in order to perfect their SAR in terms of antiviral activities.14 target compounds were synthesized in total in this part, of which 9 compounds are novel. All target compounds were assayed for their antiviral activities in vitro, including anti influenza virus A, anti COX B3, and anti HSV-2 activity. Compounds 44f (IC50:18.5μg/ml),47 (IC50:34.4μg/ml),48 (IC50:8.90μg/ml) exhibited some anti-influenza activity, but the activity was weak. Compounds 44f (IC50:3.33μg/ml),45e (IC50:18.52μg/ml),43 (IC50:17.25μg/ml),47 (IC50:14.37μg/ml) also showed some activity against COX B3 virus, but their IC50 value was much higher than that of S632A2 (0.76μg/ml) and CHX (0.09μg/ml). Only compound 45a presented some activity against HSV-2 virus, and its IC50 value (2.06μg/ml) was equal to that of CHX (1.63μg/ml) and S632A2 (3.17μg/ml), and was worthy of further research. The SAR research showed that syn isomer of aldol condensation, a conjugated system in theβside chain, especially on theβposition of carbonyl, andα,βunsaturated ketone substitutes in theβside chain favor the antiviral activities.In this paper,126 compounds (85 compounds are novel) were synthesized in total, among which 63 compounds (54 compounds are novel) were taget compounds. The structures of all target compounds were confirmed by both 1H NMR and HRMS spectrum. The synthesis, bioactivities and SAR of cajanine derivatives is the groundbreaking work in this paper, especially the discovery of anti-influenza virus activity of those compounds, and pave the way for the further research. The syntheis and antiviral activity of glutarimide derivatives is the continuation of previous work, and this research further improved the SAR of those compounds in the terms of anti virus. Meanwhile, the activity against HSV-2 virus of compounds 45a was worthy of further research. |
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