查尔酮衍生物的合成及抗炎活性研究
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摘要
查尔酮具有广泛的生物学活性。据报道查尔酮的衍生物具有抗炎作用并抑制NO的生成。前人合成的2',4',6'-(trismethoxymethoxy)chalcone (TMMC)衍生物在RAW 264.7 cell中,通过抑制NO的生成表现出了较好的抗炎作用。根据查尔酮的抗炎作用的机理我们合成了比TMMC更好的抗炎化合物。即,合成了(2E,2'E)-1,1'-(2-hydroxy-4,5,6-trimehoxy-1,3-phenylene)bis(3-phenylprop(3-phenylprop-2-en-l-one)衍生物。此类化合物设计思路是以3,4,5-trimethoxyphenol为原料,不仅具有2'-hydroxy group,而且同时具有两个α,β-unsaturated ketone group。其中,一些化合物能够很好的抑制NO的生成,并表现出了良好的抗炎活性。由于GSH降低α-hydrogen的酸性,因而A环上的2'-hydroxy group将增加GSH的Michael addition及A环上推电子基团的亲电性。我们合成的化合物中,B环上存在的强推电子基团,如4-dimethylamino group化合物表现出最弱的抗炎活性。我们猜测此机理是B环上的dimethylamino group会降低GSH的稳定性,而且氮上的电子对通过苯环会降低C-S结合力。综上,具有两个查尔酮结构的化合物的抗炎活性要高于具有一个查尔酮结构的化合物。
Chalcones have various therapeutic effects. A number of chalcone derivatives have been reported as anti-inflammatory agents and could reduce nitric oxide (NO) production by inhibition of inducible NOS protein synthase. The previously synthesized 2',4',6'-tris (methoxymethoxy) chalcone (TMMC) derivatives showed potent anti-inflammatory effects by inhibiting NO production in RAW 264.7 cells. Until now, people have made deep study of the pharmacological activity of chalcone, on this basis of that we are trying to design some more effective chalcone derivatives, namely existent of 2'-OH as well as twoα,β-unsaturated ketone group. A new series of (2E,2'E)-1,1'-(2-hydroxy-4,5,6-trimehoxy-1,3-phenylene)bis (3-phenylprop-2-en-l-one) derivatives that we designed using 3,4,5-trimethoxy phenol as the starting material, its anti-inflammatory effects via inhibition of nitric oxide production was analyzed. Some of compounds significantly showed inhibition of NO production. The 2'-OH group on the A ring elevates the electrophilicity with Michael addition of GSH and electron donating groups on the A ring stabilize the GSH adduct by decreasing the acidity of a-hydrogen. Strong electron donating groups on the B ring such as 4-dimethylamino group gave the weakest inhibition of NO production, possibly because it decreased the stability of the GSH adduct by weakening C-S bond.strength by moving the electron pair on nitrongen through an aromatic ring. The results show that the compound with dual chalcone display higher activities than that with one chalcone.
Chalcones have various therapeutic effects. A number of chalcone derivatives have been reported as anti-inflammatory agents and could reduce nitric oxide (NO) production by inhibition of inducible NOS protein synthase. The previously synthesized 2',4',6'-tris (methoxymethoxy) chalcone (TMMC) derivatives showed potent anti-inflammatory effects by inhibiting NO production in RAW 264.7 cells. Until now, people have made deep study of the pharmacological activity of chalcone, on this basis of that we are trying to design some more effective chalcone derivatives, namely existent of 2'-OH as well as twoα,β-unsaturated ketone group. A new series of (2E,2'E)-1,1'-(2-hydroxy-4,5,6-trimehoxy-1,3-phenylene)bis (3-phenylprop-2-en-l-one) derivatives that we designed using 3,4,5-trimethoxy phenol as the starting material, its anti-inflammatory effects via inhibition of nitric oxide production was analyzed. Some of compounds significantly showed inhibition of NO production. The 2'-OH group on the A ring elevates the electrophilicity with Michael addition of GSH and electron donating groups on the A ring stabilize the GSH adduct by decreasing the acidity of a-hydrogen. Strong electron donating groups on the B ring such as 4-dimethylamino group gave the weakest inhibition of NO production, possibly because it decreased the stability of the GSH adduct by weakening C-S bond.strength by moving the electron pair on nitrongen through an aromatic ring. The results show that the compound with dual chalcone display higher activities than that with one chalcone.
引文
[1]陈季武,胡天喜,朱大元.11种黄酮类化合物清除超氧阴离子的构效关系研究[J].中国药学杂志,2004,37(1)：57-58.
[2]廖头根,汪秋琴等.新型查尔酮类化合物的合成及其生物活性研究[J].有机化学,2006,26(5)：685-689.
[3]张彦文,郭宗儒.查尔酮类化合物的药理作用和构效关系[J].国外医学药学分册,1996,23(4)：218-223.
[4]Mikasicek RJ. Commonly occurring plant flavonoids have estrogenic activity. Mol Pharmacol,1993,44 (1):37-43.
[5]Edenharder R, Petersdorff I, Rauscher R, et al. Antimutagenic effects of flavonoids, chalcones and structurally related compounds on the activity of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) and other heterocyclic amine mutagenic from cooked food. Mutation Res,1993,287:261-274.
[6]WANG Y, CHAN FL, CHEN S, et al. The plantpolyphenol butein inhibits testosterone-induced proliferation in breast cancer cells expressing aromatase [J]. Life Sci,2005,77(1):39-51
[7]YAMAZAKI S, MOR ITA T, ENDO H, et al. Isoliquiritigenin suppresses pulmonary metastasis of mouse renal cell carcinoma [J]. Cancer Lett,2002,183 (1): 23-30
[8]HSU YL, KUO PL, TZENG WS, et a.l Chalcone inhibits the proliferation of human breast cancer cell by blocking cell cycle progression and inducing apoptosis [J]. Food Chem Toxicol,2006,44 (5):704-713
[9]RAFIMM, ROSEN RT, VASSL A, et al. Modulation of bc1-2 and cytotoxicity by licochalcone-A, a novel etrogemic flabonoid [J]. Anticancer Res,2000,20 (4):2653-2658.
(10)NAM NH, KM Y, YOU YJ, et al. Cytotoxic 2',5'-dihydroxychalcones with unexpected antiangiogenic activity [J]. Eur J Med Chem,2003,38 (2):179-187.
[11]XIA Y, YANG ZY, XIA P, et al. Antitumor agents part 202:novel 2'-amino chalcones:design,synthesis and biological evaluationy[J]. Bioorg Med Chem Lett, 2000,10 (8):699-701.
[12]DUCKI S,FORREST R,HADFIELD JA, et a.l Potent antimitotic and cell growth inhibitory properties of substituted chalcones [J]. Bioorg Med Chem Lett,1998,8(9): 1051-1056.
[13]PARMAR VS, BRACKEME, PH L IPPE J,et al Anti-invasive activity of alkaloids and polyphenollics in vitro[J]. Bioorg Med Chem,1997,5 (8):1609-1619.
[14]MIRANDDA CL, STEVENS JF, HELMRAICH A, et a.l Antiproliferative and cytotoxic effects of prenylated flavonoids from hops(Humuluslupulus) in human cancer cell lines[J]. Food Chem Toxicol,1999,37 (4):271-285.
[15]KUMAR SK, HAGER E, PETTIT C, et al. Design, synthesis,and evaluation of novel Boronic-Chalcone derivatives as antitumor agents[J]. J Med Chem,2003,46 (14):2813-2815.
[16]NAKAMURA C, KAWASAKIN, MIYATAKA H, et al. Synthesis and biological activities of fluorinated chalcone derivatives [J]. Bioorg Med Chem,2002, 10(3):699-706.
[17]Devi MA, Das NP, In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer Lett.1993,69(3):191-196
[18]Zhang K, Das NP. Inhibitory effects of plant polyphenols on rat liver glutathione S-transferases. Biochem Pharmacol,1994; 47 (11):2063-2068.
[19]Edwards ML, Stemerick DM, Sunkara PS, et al. Chalcones:a new class of antimitotic agents. J Med Chem,1990,33 (7):1948-1954.
[20]Kagechika H, Kawachi E, Hashimoto Y, et al. Retinobenzoic acids. Structure-activity relationships of chalcone-4-carboxylic acids and flavone-4'-carboxylic acids. J Med Chem,1989,32 (4):834-840.
[21]BOCEK P, BANDEIRA FALCAO CA, LEAL PC, et al. Synthesis of chalcone analogues with increased antileishmanial activity [J]. Bioorg Med Chem,2006,14 (5):1538-1545.
[22]LIUM, WLAIRAT P, CROFTSL, et al. Structure-activity relationships of antileishmanial and antimalarial halcones[J]. Bioorg Med Chem,2003,11 (13):2729-2738.
[23]WU X, WLAIRAT P, GO ML. Antimalarial activity of ferrocenyl chalcones[J]. Bioorg Med Chem Lett,2002,12 (17):2299-2302.
[24]UCHIUMIF, HAT ANNO T, ITO H, et al. Transcriptional suppression of the HIV promoter by natural compounds[J]. Antiviral Res,2003,58 (1):89-98.
[25]WU JH, WANG XH, YI YH, et al. Anti-AIDS agents 54. A potent Anti-HIV chalcone and flabonoids from Genus Desm os[J]. Bioorg Med Chem Lett,2003,13 (10):1813-1815.
[26]CHEENPRACHA S, KARALAIC, PONGL MANONT C, et al. Anti-HIV-1 protease activity of compounds from B oesenbergia pandurata[J]. Bioorg Med Chem, 2006,14 (6):1710-1714.
[27]DENG J, KELLEYJA, BARCHIJJ, et al. Mining the NCI anti-viral compounds for HIV-1 integrase inhitors[J]. Bioorg Med Chem,2006,14 (11):3785-3792.
[28]NIEL SEN SF, BOESEN T, LARSEN M, et al. Antibacterial chalcones-bioisosteric replacement of the 4'-hydroxy group[J]. Bioorg Med Chem,2004,12(11): 3047-3054.
[29]LOPEZ SN, CASTELL IMV, ZACCHNO SA, et al. In vitro antifungal evaluation and structure-activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall[J]. Bioorg Med Chem,2001,9 (8):1999-2013.
[30]LALL N, HUSSE N AA, MEYER JJ, et al. Antiriral and antituberculous activity of Helichrysum melanaane consitituents[J]. Fitoterapia,2006,77 (3):230-232.
[31]LIN YM, ZHOU Y, FLAVN MT, et al. Chalcone and flavonoids as anti-tubercubosis agent[J]. Bioorg Med Chem,2002,10 (8):2795-2802.
[32]HERENCIA F, FERRAND IZML, UBEDA A, et al. Nover anti-inflamatory chalcone derivatives inhibit the induciton of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages[J]. FEBS Lett,1999,453 (12): 129-134.
[33]HERENCA F, FERRAND IZ ML, UBEDA A, et al Synthesis and anti-inflammatory activity of chalcone derivatives[J]. Bioorg Med Chem Lett,1998,8 (10):1169-1174.
[34]TUCHNDA P, REUTRAKUL V, CLAESON P, et al. Anti-inflammatory cyclohexenyl chalcone derivatives in B oesenbergia pandurata[J]. Phytochem istry, 2002,59 (2):169-173.
[35]KO HH, TSAO LT, YU KL, et al. Structure-activity relationship studies on chalcone derivatives:the potent inhibition of chemical mediators release[J]. Bioorg Med Chem,2003,11 (1):105-111.
[36]ZHAO LM, JN HS, SUN LP, et al. Synthesis and evaluation of antiplatelet activity of tribydroxychalcone derivatives [J]. Bioorg Med Chem Lett,2005,15 (22): 5027-5029.
[37]Limasset B, Doucen C, Dore JC, et al. Effects of flabonoids on the release of reactive oxygen species by stimulated human neutrophils. Biochem Pharmacal,1993, 46(7):1257-1271.
[38]Murakami S, Muramatsu M, Aihara H, et al. Inhibition of gastric H+/K+-ATPase by the antiulcer agent, Sofalcone. Biochem Pharmacol,1991,42 (7):1447-1451.
[39]Kuppusamy UR, Das NP. Effects of flabonoids on cyclic AMP phosphodiesterase and lipid mobilization in rat adipocytes. Biochem Pharmacol, 1992,44(7):1307-1315.
[40]Harborne JB. Nature, distribution, and function of plant flabonoids. In:Cody V, Middleton E, Harborne J, eds. Plant flabonoids in biology and medicine Ⅱ. Biochemical celluar and medicinal properties. New York:Alan R Liss. 1988:388-402.
[41]杨立,沈凤嘉.甘草素与异甘草素的合成.药学学报,1994,29(11)：877-880.
[42]LAL BER TE R. Antherm in tie activihes of chalcones and related compounds[J]. Can J Pharm Sci,1967,2 (2):37-43.
[43]何克勤,程桂芳,奚凤德等.查尔酮类化合物对过敏性慢反应物质拮抗作用的构效关系[J].药学学报,1996,11：878-880.
[44]MARTIN C R. Structure, function, and regulation of the chalone synthease[J]. 1993,147:233-284.
[45]方正,唐伟方,徐芳.萘丁美酮的合成工艺改进[J].中国药科大学学报,2004,35(1)：90-91.
[46]楼定忠,朱坡,刘泽贵.萘丁美酮合成路线图解[J].中国医药工业杂志,1996,27(5)：238-239.
[47]艾亨俭,李文玉.萘普酮的又一合成[J].中国医药工业杂志,1985,16(11)：509-510.
[2]廖头根,汪秋琴等.新型查尔酮类化合物的合成及其生物活性研究[J].有机化学,2006,26(5)：685-689.
[3]张彦文,郭宗儒.查尔酮类化合物的药理作用和构效关系[J].国外医学药学分册,1996,23(4)：218-223.
[4]Mikasicek RJ. Commonly occurring plant flavonoids have estrogenic activity. Mol Pharmacol,1993,44 (1):37-43.
[5]Edenharder R, Petersdorff I, Rauscher R, et al. Antimutagenic effects of flavonoids, chalcones and structurally related compounds on the activity of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) and other heterocyclic amine mutagenic from cooked food. Mutation Res,1993,287:261-274.
[6]WANG Y, CHAN FL, CHEN S, et al. The plantpolyphenol butein inhibits testosterone-induced proliferation in breast cancer cells expressing aromatase [J]. Life Sci,2005,77(1):39-51
[7]YAMAZAKI S, MOR ITA T, ENDO H, et al. Isoliquiritigenin suppresses pulmonary metastasis of mouse renal cell carcinoma [J]. Cancer Lett,2002,183 (1): 23-30
[8]HSU YL, KUO PL, TZENG WS, et a.l Chalcone inhibits the proliferation of human breast cancer cell by blocking cell cycle progression and inducing apoptosis [J]. Food Chem Toxicol,2006,44 (5):704-713
[9]RAFIMM, ROSEN RT, VASSL A, et al. Modulation of bc1-2 and cytotoxicity by licochalcone-A, a novel etrogemic flabonoid [J]. Anticancer Res,2000,20 (4):2653-2658.
(10)NAM NH, KM Y, YOU YJ, et al. Cytotoxic 2',5'-dihydroxychalcones with unexpected antiangiogenic activity [J]. Eur J Med Chem,2003,38 (2):179-187.
[11]XIA Y, YANG ZY, XIA P, et al. Antitumor agents part 202:novel 2'-amino chalcones:design,synthesis and biological evaluationy[J]. Bioorg Med Chem Lett, 2000,10 (8):699-701.
[12]DUCKI S,FORREST R,HADFIELD JA, et a.l Potent antimitotic and cell growth inhibitory properties of substituted chalcones [J]. Bioorg Med Chem Lett,1998,8(9): 1051-1056.
[13]PARMAR VS, BRACKEME, PH L IPPE J,et al Anti-invasive activity of alkaloids and polyphenollics in vitro[J]. Bioorg Med Chem,1997,5 (8):1609-1619.
[14]MIRANDDA CL, STEVENS JF, HELMRAICH A, et a.l Antiproliferative and cytotoxic effects of prenylated flavonoids from hops(Humuluslupulus) in human cancer cell lines[J]. Food Chem Toxicol,1999,37 (4):271-285.
[15]KUMAR SK, HAGER E, PETTIT C, et al. Design, synthesis,and evaluation of novel Boronic-Chalcone derivatives as antitumor agents[J]. J Med Chem,2003,46 (14):2813-2815.
[16]NAKAMURA C, KAWASAKIN, MIYATAKA H, et al. Synthesis and biological activities of fluorinated chalcone derivatives [J]. Bioorg Med Chem,2002, 10(3):699-706.
[17]Devi MA, Das NP, In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer Lett.1993,69(3):191-196
[18]Zhang K, Das NP. Inhibitory effects of plant polyphenols on rat liver glutathione S-transferases. Biochem Pharmacol,1994; 47 (11):2063-2068.
[19]Edwards ML, Stemerick DM, Sunkara PS, et al. Chalcones:a new class of antimitotic agents. J Med Chem,1990,33 (7):1948-1954.
[20]Kagechika H, Kawachi E, Hashimoto Y, et al. Retinobenzoic acids. Structure-activity relationships of chalcone-4-carboxylic acids and flavone-4'-carboxylic acids. J Med Chem,1989,32 (4):834-840.
[21]BOCEK P, BANDEIRA FALCAO CA, LEAL PC, et al. Synthesis of chalcone analogues with increased antileishmanial activity [J]. Bioorg Med Chem,2006,14 (5):1538-1545.
[22]LIUM, WLAIRAT P, CROFTSL, et al. Structure-activity relationships of antileishmanial and antimalarial halcones[J]. Bioorg Med Chem,2003,11 (13):2729-2738.
[23]WU X, WLAIRAT P, GO ML. Antimalarial activity of ferrocenyl chalcones[J]. Bioorg Med Chem Lett,2002,12 (17):2299-2302.
[24]UCHIUMIF, HAT ANNO T, ITO H, et al. Transcriptional suppression of the HIV promoter by natural compounds[J]. Antiviral Res,2003,58 (1):89-98.
[25]WU JH, WANG XH, YI YH, et al. Anti-AIDS agents 54. A potent Anti-HIV chalcone and flabonoids from Genus Desm os[J]. Bioorg Med Chem Lett,2003,13 (10):1813-1815.
[26]CHEENPRACHA S, KARALAIC, PONGL MANONT C, et al. Anti-HIV-1 protease activity of compounds from B oesenbergia pandurata[J]. Bioorg Med Chem, 2006,14 (6):1710-1714.
[27]DENG J, KELLEYJA, BARCHIJJ, et al. Mining the NCI anti-viral compounds for HIV-1 integrase inhitors[J]. Bioorg Med Chem,2006,14 (11):3785-3792.
[28]NIEL SEN SF, BOESEN T, LARSEN M, et al. Antibacterial chalcones-bioisosteric replacement of the 4'-hydroxy group[J]. Bioorg Med Chem,2004,12(11): 3047-3054.
[29]LOPEZ SN, CASTELL IMV, ZACCHNO SA, et al. In vitro antifungal evaluation and structure-activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall[J]. Bioorg Med Chem,2001,9 (8):1999-2013.
[30]LALL N, HUSSE N AA, MEYER JJ, et al. Antiriral and antituberculous activity of Helichrysum melanaane consitituents[J]. Fitoterapia,2006,77 (3):230-232.
[31]LIN YM, ZHOU Y, FLAVN MT, et al. Chalcone and flavonoids as anti-tubercubosis agent[J]. Bioorg Med Chem,2002,10 (8):2795-2802.
[32]HERENCIA F, FERRAND IZML, UBEDA A, et al. Nover anti-inflamatory chalcone derivatives inhibit the induciton of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages[J]. FEBS Lett,1999,453 (12): 129-134.
[33]HERENCA F, FERRAND IZ ML, UBEDA A, et al Synthesis and anti-inflammatory activity of chalcone derivatives[J]. Bioorg Med Chem Lett,1998,8 (10):1169-1174.
[34]TUCHNDA P, REUTRAKUL V, CLAESON P, et al. Anti-inflammatory cyclohexenyl chalcone derivatives in B oesenbergia pandurata[J]. Phytochem istry, 2002,59 (2):169-173.
[35]KO HH, TSAO LT, YU KL, et al. Structure-activity relationship studies on chalcone derivatives:the potent inhibition of chemical mediators release[J]. Bioorg Med Chem,2003,11 (1):105-111.
[36]ZHAO LM, JN HS, SUN LP, et al. Synthesis and evaluation of antiplatelet activity of tribydroxychalcone derivatives [J]. Bioorg Med Chem Lett,2005,15 (22): 5027-5029.
[37]Limasset B, Doucen C, Dore JC, et al. Effects of flabonoids on the release of reactive oxygen species by stimulated human neutrophils. Biochem Pharmacal,1993, 46(7):1257-1271.
[38]Murakami S, Muramatsu M, Aihara H, et al. Inhibition of gastric H+/K+-ATPase by the antiulcer agent, Sofalcone. Biochem Pharmacol,1991,42 (7):1447-1451.
[39]Kuppusamy UR, Das NP. Effects of flabonoids on cyclic AMP phosphodiesterase and lipid mobilization in rat adipocytes. Biochem Pharmacol, 1992,44(7):1307-1315.
[40]Harborne JB. Nature, distribution, and function of plant flabonoids. In:Cody V, Middleton E, Harborne J, eds. Plant flabonoids in biology and medicine Ⅱ. Biochemical celluar and medicinal properties. New York:Alan R Liss. 1988:388-402.
[41]杨立,沈凤嘉.甘草素与异甘草素的合成.药学学报,1994,29(11)：877-880.
[42]LAL BER TE R. Antherm in tie activihes of chalcones and related compounds[J]. Can J Pharm Sci,1967,2 (2):37-43.
[43]何克勤,程桂芳,奚凤德等.查尔酮类化合物对过敏性慢反应物质拮抗作用的构效关系[J].药学学报,1996,11：878-880.
[44]MARTIN C R. Structure, function, and regulation of the chalone synthease[J]. 1993,147:233-284.
[45]方正,唐伟方,徐芳.萘丁美酮的合成工艺改进[J].中国药科大学学报,2004,35(1)：90-91.
[46]楼定忠,朱坡,刘泽贵.萘丁美酮合成路线图解[J].中国医药工业杂志,1996,27(5)：238-239.
[47]艾亨俭,李文玉.萘普酮的又一合成[J].中国医药工业杂志,1985,16(11)：509-510.