天然黄酮、黄烷、二氢高异黄酮及其相关化合物的合成与抗肿瘤活性研究
|
摘要
恶性肿瘤严重威胁人类健康,所导致的死亡人数高居各类疾病的前列。抗肿瘤活性天然化合物在肿瘤治疗中发挥着重要作用。近年来,基于天然化合物Combretastatin A-4(CA-4)发展起来的血管破坏化合物引起了广泛注意。这类化合物通过与微管蛋白秋水仙碱位点结合导致肿瘤血管内皮细胞骨架和形态发生变化,形成血栓,中断肿瘤细胞血液供应,达到杀灭肿瘤细胞的目的,与传统抗癌药物相比具有明显优势。在过去的十余年间,合成了数百个该类化合物,但是这些化合物只是针对CA-4进行改造,变化幅度小,结构类型单一,不利于血管破坏类化合物的构效关系研究。
本论文将血管破坏化合物与传统中药结合,发挥中药研究的优势,在中药来源天然化合物中发现新结构类型的血管破坏类化合物。经文献调研发现,黄酮类化合物具有一定的抗肿瘤作用,但是机理研究不清晰,而且其在结构上与CA-4类化合物存在一定的相似性。以天然产物3',4',5',7,8-五甲氧基黄酮、3',4',7,8-四甲氧基-5'-羟基-黄酮、(S)-3',4',5',7,8-五甲氧基黄烷、(S)-3',4',7,8-四甲氧基-5'-羟基-黄烷和(S)-4'-甲氧基-7,8-亚甲二氧基二氢高异黄酮为基础,结合CA-4等血管破坏化合物结构特点,我们设计了黄酮、黄烷、9-氧代高异黄酮、高异黄酮、二氢高异黄酮、4-羟基高异黄烷和高异黄烷七类共计67个化合物。
以焦性没食子酸和各种苯甲酸为原料,经过乙酰化、烷基化、成酯反应、Baker-Venkataraman重排和分子内脱水等反应完成了两个天然黄酮3',4',5',7,8-五甲氧基黄酮、3',4',7,8-四甲氧基-5'-羟基黄酮和9个相关化合物的合成。两个天然黄酮的总收率达到31.9%和24.0%。
在合成中,发现了经钯碳催化的氢化氢解反应将黄酮直接转化到黄烷的新方法,分别以81.9%和82.6%的收率完成了相应黄酮到天然黄烷混旋体(±)-5'-羟基-3',4',7,8-四甲氧基黄烷和(±)-3',4',5',7,8-五甲氧基黄烷的转化。
以焦性没食子酸和各种苯甲酸为原料,经过乙酰化、烷基化、成酯、Baker-Venkataraman重排和“一碳延伸”等反应完成了8个9-氧代高异黄酮类目标化合物的制备。
以焦性没食子酸和各种苯甲醛为原料,经乙酰化、选择性O-烷基化、羟醛缩合、还原和环合等反应制备了13个高异黄酮目标化合物。
以高异黄酮为原料,经Raney Ni催化氢化反应完成了天然二氢高异黄酮(±)-7,8-亚甲二氧基-4'-甲氧基-二氢高异黄酮和9个相关化合物的合成,天然产物混旋体的总收率为4.O%。
将钯碳催化氢化与超声催化相结合,首次发现了超声条件下钯碳催化氢化将高异黄酮转化为4-羟基高异黄烷的新反应,采用此方法完成了14个4-羟基高异黄烷目标化合物的合成。
首次发现了超声条件下钯碳催化氢化/氢解反应将高异黄酮转化为高异黄烷的新反应,实现了高异黄酮到高异黄烷的高收率直接转化,完成了10个高异黄烷目标化合物的合成。
在还原查尔酮合成二氢查尔酮的过程中,发现超声条件下Zn/HOAc体系能够选择性快速还原与羰基共轭的碳碳双键。
合成的目标化合物结构经MS,(1)H-NMR和(13)C-NMR确证。
采用MTT法使用SGC-7901、BEL-7402和HeLa等肿瘤细胞株完成了40个目标化合物和4个黄酮的合成中间体的抗肿瘤活性测试。3',4',5',7,8-五甲氧基-9-氧代高异黄酮(ZLC-01)、3'-羟基-4',7,8-三甲氧基高异黄酮(ZLD-05)、3',4',5'-三甲氧基-7,8-亚甲二氧基二氢高异黄酮(ZLE-07)和3'-羟基-4'-甲氧基-7,8-亚甲二氧基二氢高异黄酮(ZLE-09)、3',4',5',7,8-五甲氧基高异黄烷(ZLG-01)、3'-羟基-4',7,8-三甲氧基高异黄烷(ZLG-05)和3'-羟基-4'-甲氧基-7,8-亚甲二氧基高异黄烷(ZLG-10)活性较好。
七类化合物中高异黄烷化合物活性普遍较好;所设计的目标化合物的B环与CA-4的A环相同时抗肿瘤活性得到一定程度增加,与CA-4的B环相同时抗肿瘤活性进一步提高;具备高异黄烷骨架且B环与CA-4的B环相同的化合物ZLG-10半数抑制浓度达到10nM数量级,与CA-4接近。ZLB-01和ZLG-10的机理研究显示,它们的抗肿瘤活性与G2/M周期阻滞有关,作用特征也与CA-4相似。
Cancer is a leading cause of death worldwide.It has accounted for 7.9 million deaths (around 13%of all death) in 2007 and deaths from cancer are projected to continue rising,with an estimated 12 million deaths in 2030.Natural anticancer agents from plant kingdom play important roles in cancer cure.Vascular disrupting agents(VDAs),a kind of compounds based on a natural product combretastatin A-4(CA-4),have been reported to show potential anticancer activity.They could cause cytoskeletal and morphological changes in endothelial cells via binding to colchicines-binding site in tubulin,which increase vascular permeability and disrupt tumor blood flow,leading to extensive ischemie necrosis in areas that are often resistant to conventional anti-cancer treatments.During the past years,hundreads of VDAs had been designed and synthesized based on the skeleton of CA-4.However,these analogues were well districted to CA-4,which was not beneficial to SAR study of VDAs.
In our research program directed toward novel VDAs in traditional Chinese medicines,we identified flavonoids to be ideal targets due to their definite antieancer activity,unclear mechanism and similar structure to CA-4.Therefore,67 compounds distributed into 7 kinds of flavonoids(flavone,flavan,9-oxo-homoisoflavone,homoisoflavone,homoisoflavonone, homoisoflavan 4-ol,homoisoflavan)were designed based on five natural products, 7,8,3',4',5'-pentamethoxyflavone,5'-hydroxy-7,8,3',4'-tertramethoxyflavone,(S)-7,8,3',4',5'-pentamethoxyflavane,(S)-5'-hydroxy-7,8,3',4'-tertramethoxyflavane and(S)-4'-methoxy-7,8-methylenedioxyhomoisoflavanone according to the structures of CA-4 and its analogues.
The synthesis of flavones were furnished from commercially available benzene-1,2,3-triol and(un)substituted benzoic acid via acetylation,selective di-methylation,esterification and Baker-Venkataraman rearrangement,etc.The two natural flavones 7,8,3',4',5'-pentamethoxy-flavone, 5'-hydroxy-7,8,3',4'-tertramethoxyflavone had thus been obtained in 31.9%and 24.0% overall yield.Other nine flavones were prepared by the same method.
During the synthesis,a straightforward synthetic procedure of flavans via Pd-C catalysed hydogenation/hydrogenolysis of corresponding flavones was developed.The two natural flavan racemates 7,8,3',4',5'-pentamethoxy-flavan and 5'-hydroxy-7,8,3',4'-tertramethoxyflavan were obtained from corresponding flavones in 81.9%,82.6%yield,respectively.
The eight 9-oxo-homoisoflavones were synthesized from benzene-1,2,3-triol and (un)substituted benzoic acid via acetylation,selective di-methylation,esterification, Baker-Venkataraman rearrangement and“one carbon extention”reaction,etc.
The synthesis of homoisoflavones commenced with the commercially available benzene-1,2,3-triol.After acetylation and alkylation of benzene-1,2,3-triol,acetophenone intermediates were obtained,which reacted with benzaldehydes giving chalcones.Hydrogenation of chalcones and then treatment with DMF-DMA furnished the synthesis of 13 homoisoflavones.
Homoisoflavanones were prepared via Raney Ni catalyzed hydogenation of corresponding homoisoflavones.The synthesis of the natural homoisoflavanone racemates 3-(4'-methoxy-benzyl) -7,8-methylenedioxy-homoisoflavanone was achieved in 4.0%.Eight Homoisoflavanones were also prepared.
The approach for the conversion of homoisoflavones into homoisoflavan 4-ols directly through Pd/C catalyzed hydogenation under ultrasound was developed for the first time.14 homoisoflavan 4-ols were prepared by this method.
It was also the first time that homoisoflavans had been synthesized via Pd/C catalyzed hydogenation/hydrogenolysis of homoisoflavones directly under ultrasound.10 homoisoflavans were prepared by this method.
During the synthesis of dihydrochalcone intermediates,it's found that Zn/HOAc could reduce the double bond conjugated with carbonyl groups in chalcones under ultrasound selectively and rapidly.
The target compounds were characterized by the applications of MS,~1H-NMR and ~(13)C-NMR.
40 target compounds and 4 synthetic intermediates were evaluated by MTT assay for their in vitro antitumor activities against human SGC-7901,BEL-7402,HeLa,etc.7,8,3',4',5'-pentamethoxyflavane (ZLB-01),7,8,3',4',5'- pentamethoxy-9-oxo-homoisoflavone(ZLC-01), 3'-hydroxy-4',7,8-trimethoxyhomoisoflavone(ZLD-05),3',4',5'-trimethoxy-7,8-methylene dioxyhomoisoflavanone(ZLE-07)and 3'-hydroxy-4'-methoxy-7,8-methylenedioxy homoisoflavanone(ZLE-09),7,8,3',4',5'-pentamethoxyhomoisoflavan(ZLG-01), 3'-hydroxy-4',7,8-trimethoxyhomoisoflavan(ZLG-05)and 3'-hydroxy-4'-methoxy-7,8-methylenedioxyhomoisoflavan (ZLG-10) possessed good in vitro antitumor activity.
The homoisoflavan compounds were proved to be more potential among the seven kinds of flavonoids.In addition,it's found that replacement of ring B in the target compounds with 3,4,5-trimethoxyphenyl(the fragment A of CA-4) or 3-hydroxy-4-methoxyphenyl(the fragment B of CA-4),especially the latter one,led to the increase of antitumor activity.The IC_(50) values of ZLG-10(3'-hydroxy-4'-methoxy-7,8-methylenedioxy-homoisoflavan),ranged from 19 nM to 97 nM.The mechanism research of ZLB-01 and ZLG-10 proved that their anti-proliferative effects were associated with cell cycle arrest in G2/M phase,which was highly similar to the effect of CA-4.
本论文将血管破坏化合物与传统中药结合,发挥中药研究的优势,在中药来源天然化合物中发现新结构类型的血管破坏类化合物。经文献调研发现,黄酮类化合物具有一定的抗肿瘤作用,但是机理研究不清晰,而且其在结构上与CA-4类化合物存在一定的相似性。以天然产物3',4',5',7,8-五甲氧基黄酮、3',4',7,8-四甲氧基-5'-羟基-黄酮、(S)-3',4',5',7,8-五甲氧基黄烷、(S)-3',4',7,8-四甲氧基-5'-羟基-黄烷和(S)-4'-甲氧基-7,8-亚甲二氧基二氢高异黄酮为基础,结合CA-4等血管破坏化合物结构特点,我们设计了黄酮、黄烷、9-氧代高异黄酮、高异黄酮、二氢高异黄酮、4-羟基高异黄烷和高异黄烷七类共计67个化合物。
以焦性没食子酸和各种苯甲酸为原料,经过乙酰化、烷基化、成酯反应、Baker-Venkataraman重排和分子内脱水等反应完成了两个天然黄酮3',4',5',7,8-五甲氧基黄酮、3',4',7,8-四甲氧基-5'-羟基黄酮和9个相关化合物的合成。两个天然黄酮的总收率达到31.9%和24.0%。
在合成中,发现了经钯碳催化的氢化氢解反应将黄酮直接转化到黄烷的新方法,分别以81.9%和82.6%的收率完成了相应黄酮到天然黄烷混旋体(±)-5'-羟基-3',4',7,8-四甲氧基黄烷和(±)-3',4',5',7,8-五甲氧基黄烷的转化。
以焦性没食子酸和各种苯甲酸为原料,经过乙酰化、烷基化、成酯、Baker-Venkataraman重排和“一碳延伸”等反应完成了8个9-氧代高异黄酮类目标化合物的制备。
以焦性没食子酸和各种苯甲醛为原料,经乙酰化、选择性O-烷基化、羟醛缩合、还原和环合等反应制备了13个高异黄酮目标化合物。
以高异黄酮为原料,经Raney Ni催化氢化反应完成了天然二氢高异黄酮(±)-7,8-亚甲二氧基-4'-甲氧基-二氢高异黄酮和9个相关化合物的合成,天然产物混旋体的总收率为4.O%。
将钯碳催化氢化与超声催化相结合,首次发现了超声条件下钯碳催化氢化将高异黄酮转化为4-羟基高异黄烷的新反应,采用此方法完成了14个4-羟基高异黄烷目标化合物的合成。
首次发现了超声条件下钯碳催化氢化/氢解反应将高异黄酮转化为高异黄烷的新反应,实现了高异黄酮到高异黄烷的高收率直接转化,完成了10个高异黄烷目标化合物的合成。
在还原查尔酮合成二氢查尔酮的过程中,发现超声条件下Zn/HOAc体系能够选择性快速还原与羰基共轭的碳碳双键。
合成的目标化合物结构经MS,(1)H-NMR和(13)C-NMR确证。
采用MTT法使用SGC-7901、BEL-7402和HeLa等肿瘤细胞株完成了40个目标化合物和4个黄酮的合成中间体的抗肿瘤活性测试。3',4',5',7,8-五甲氧基-9-氧代高异黄酮(ZLC-01)、3'-羟基-4',7,8-三甲氧基高异黄酮(ZLD-05)、3',4',5'-三甲氧基-7,8-亚甲二氧基二氢高异黄酮(ZLE-07)和3'-羟基-4'-甲氧基-7,8-亚甲二氧基二氢高异黄酮(ZLE-09)、3',4',5',7,8-五甲氧基高异黄烷(ZLG-01)、3'-羟基-4',7,8-三甲氧基高异黄烷(ZLG-05)和3'-羟基-4'-甲氧基-7,8-亚甲二氧基高异黄烷(ZLG-10)活性较好。
七类化合物中高异黄烷化合物活性普遍较好;所设计的目标化合物的B环与CA-4的A环相同时抗肿瘤活性得到一定程度增加,与CA-4的B环相同时抗肿瘤活性进一步提高;具备高异黄烷骨架且B环与CA-4的B环相同的化合物ZLG-10半数抑制浓度达到10nM数量级,与CA-4接近。ZLB-01和ZLG-10的机理研究显示,它们的抗肿瘤活性与G2/M周期阻滞有关,作用特征也与CA-4相似。
Cancer is a leading cause of death worldwide.It has accounted for 7.9 million deaths (around 13%of all death) in 2007 and deaths from cancer are projected to continue rising,with an estimated 12 million deaths in 2030.Natural anticancer agents from plant kingdom play important roles in cancer cure.Vascular disrupting agents(VDAs),a kind of compounds based on a natural product combretastatin A-4(CA-4),have been reported to show potential anticancer activity.They could cause cytoskeletal and morphological changes in endothelial cells via binding to colchicines-binding site in tubulin,which increase vascular permeability and disrupt tumor blood flow,leading to extensive ischemie necrosis in areas that are often resistant to conventional anti-cancer treatments.During the past years,hundreads of VDAs had been designed and synthesized based on the skeleton of CA-4.However,these analogues were well districted to CA-4,which was not beneficial to SAR study of VDAs.
In our research program directed toward novel VDAs in traditional Chinese medicines,we identified flavonoids to be ideal targets due to their definite antieancer activity,unclear mechanism and similar structure to CA-4.Therefore,67 compounds distributed into 7 kinds of flavonoids(flavone,flavan,9-oxo-homoisoflavone,homoisoflavone,homoisoflavonone, homoisoflavan 4-ol,homoisoflavan)were designed based on five natural products, 7,8,3',4',5'-pentamethoxyflavone,5'-hydroxy-7,8,3',4'-tertramethoxyflavone,(S)-7,8,3',4',5'-pentamethoxyflavane,(S)-5'-hydroxy-7,8,3',4'-tertramethoxyflavane and(S)-4'-methoxy-7,8-methylenedioxyhomoisoflavanone according to the structures of CA-4 and its analogues.
The synthesis of flavones were furnished from commercially available benzene-1,2,3-triol and(un)substituted benzoic acid via acetylation,selective di-methylation,esterification and Baker-Venkataraman rearrangement,etc.The two natural flavones 7,8,3',4',5'-pentamethoxy-flavone, 5'-hydroxy-7,8,3',4'-tertramethoxyflavone had thus been obtained in 31.9%and 24.0% overall yield.Other nine flavones were prepared by the same method.
During the synthesis,a straightforward synthetic procedure of flavans via Pd-C catalysed hydogenation/hydrogenolysis of corresponding flavones was developed.The two natural flavan racemates 7,8,3',4',5'-pentamethoxy-flavan and 5'-hydroxy-7,8,3',4'-tertramethoxyflavan were obtained from corresponding flavones in 81.9%,82.6%yield,respectively.
The eight 9-oxo-homoisoflavones were synthesized from benzene-1,2,3-triol and (un)substituted benzoic acid via acetylation,selective di-methylation,esterification, Baker-Venkataraman rearrangement and“one carbon extention”reaction,etc.
The synthesis of homoisoflavones commenced with the commercially available benzene-1,2,3-triol.After acetylation and alkylation of benzene-1,2,3-triol,acetophenone intermediates were obtained,which reacted with benzaldehydes giving chalcones.Hydrogenation of chalcones and then treatment with DMF-DMA furnished the synthesis of 13 homoisoflavones.
Homoisoflavanones were prepared via Raney Ni catalyzed hydogenation of corresponding homoisoflavones.The synthesis of the natural homoisoflavanone racemates 3-(4'-methoxy-benzyl) -7,8-methylenedioxy-homoisoflavanone was achieved in 4.0%.Eight Homoisoflavanones were also prepared.
The approach for the conversion of homoisoflavones into homoisoflavan 4-ols directly through Pd/C catalyzed hydogenation under ultrasound was developed for the first time.14 homoisoflavan 4-ols were prepared by this method.
It was also the first time that homoisoflavans had been synthesized via Pd/C catalyzed hydogenation/hydrogenolysis of homoisoflavones directly under ultrasound.10 homoisoflavans were prepared by this method.
During the synthesis of dihydrochalcone intermediates,it's found that Zn/HOAc could reduce the double bond conjugated with carbonyl groups in chalcones under ultrasound selectively and rapidly.
The target compounds were characterized by the applications of MS,~1H-NMR and ~(13)C-NMR.
40 target compounds and 4 synthetic intermediates were evaluated by MTT assay for their in vitro antitumor activities against human SGC-7901,BEL-7402,HeLa,etc.7,8,3',4',5'-pentamethoxyflavane (ZLB-01),7,8,3',4',5'- pentamethoxy-9-oxo-homoisoflavone(ZLC-01), 3'-hydroxy-4',7,8-trimethoxyhomoisoflavone(ZLD-05),3',4',5'-trimethoxy-7,8-methylene dioxyhomoisoflavanone(ZLE-07)and 3'-hydroxy-4'-methoxy-7,8-methylenedioxy homoisoflavanone(ZLE-09),7,8,3',4',5'-pentamethoxyhomoisoflavan(ZLG-01), 3'-hydroxy-4',7,8-trimethoxyhomoisoflavan(ZLG-05)and 3'-hydroxy-4'-methoxy-7,8-methylenedioxyhomoisoflavan (ZLG-10) possessed good in vitro antitumor activity.
The homoisoflavan compounds were proved to be more potential among the seven kinds of flavonoids.In addition,it's found that replacement of ring B in the target compounds with 3,4,5-trimethoxyphenyl(the fragment A of CA-4) or 3-hydroxy-4-methoxyphenyl(the fragment B of CA-4),especially the latter one,led to the increase of antitumor activity.The IC_(50) values of ZLG-10(3'-hydroxy-4'-methoxy-7,8-methylenedioxy-homoisoflavan),ranged from 19 nM to 97 nM.The mechanism research of ZLB-01 and ZLG-10 proved that their anti-proliferative effects were associated with cell cycle arrest in G2/M phase,which was highly similar to the effect of CA-4.
引文
[1].http://www.who.int/mediacentre
[2].蔡仲曦,林华.我国抗肿瘤药物调查与分析.中国新药杂志.2001,10(3),233-236.
[3].陆江海,李秀兰,刘沁率,赵玉英.天然产物与药物的发现.国外医药·植物药分册.2000,15(2),47-79.
[4].Wani,M.C.;Taylor,H.L.;Wall,M.E.;et al.Plant antitumor agents.Ⅳ.Isolation and structure of taxol,a novel antileukemic and antitumor agent from Taxus brevifolia.Journal of the American Chemical Society.1971,93(9),2325-2327.
[5].莫晓媚,李静,耿美玉.DNA 拓扑异构酶与抗肿瘤.中国药理学通报.2007,23(1),20-23。
[6].Wall,M.E;Wani,M.C;Cook,C.E;et al.Antitumor agent I.The isolation and structure of Camptothecin,a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate.Journal of American Chemical Society.1966,88(16),3888-3890.
[7].潘显道,王存英.天然抗肿瘤药喜树碱衍生物的研究进展.药学学报.2003,38(9),715-720.
[8].郭仕华,娄红祥,贺艳丽.天然抗肿瘤药物的研究进展.国外医药.植物药分册.2005,20(5),190-196.
[9].Takaoka,M.Phenolic substance of white hellebore(Veratrum grandiflorum Loes fil.).Ⅲ.Constitution of resveratrol.Nippon Kagaku Kaishi.(1921-1947).1940,61,30-4.
[10].Tseng,S.H;Lin,S.M;Chen,J.C;et al.Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats.Clinical Cancer Research.2004,10(6),2190-2202.
[11].Lin,M.T;Yen,M.L;Lin,C.Y;et al.Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation.Molecular Pharmacology.2003,64(5),1029-1036.
[12].Pettit,G.R;Singh,S.B;Hamel,E;et al.Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4.Experientia.1989,45,209-211.
[13].Kanthou,C;Tozer,G.M.The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells.Blood.2002,99(6),2060-2069.
[14].Kador,P.F;Blessing K;Randazzo J;et al.Evaluation of the vascular targeting agent combretastatin a-4prodrug on retinal neovascularization in the galactose-fed dog.Journal of ocular pharmacology and therapeutics:the official journal of the Association for Ocular Pharmacology and Therapeutics.2007,23(2),132-142.
[15].Pinney,K.G;Jelinek,C;Evardsen,K;et al.The discovery and development of the combretastatins.In Anticancer Agents from Natural Products;Cragg GM,Kingston DGI,Newman D J,Eds.;Brunner-Routledge Psychology Press,Taylor & Francis Group:Boca Raton,FL,2005;pp 23-46.
[16].Brooks,A.C;Kanthou,C;Cook,I.H;et al.The vascular targeting agent combretastatin A-4-phosphate induces neutrophil recruitment to endothelial cells in vitro.Anticancer Research 2003,23,3199-3206.
[17].Siemann,D.W.;Shi,W.Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors.International Journal of Radiation Oncology,Biology,Physics.2004,60(4),1233-1240.
[18].许旭东,胡晓茹,杨峻山.抗肿瘤药用植物有效成分研究概况.中国中药杂志.2008,33,2079-2081.
[19].李云霞,贺文智,索全伶,等.黄酮类化合物活性及构效关系研究概况.内蒙古石油化工.2004,30(2),10-12.
[20].方从兵,宛晓春,江昌俊.黄酮类化合物生物合成的研究进展.安徽农业大学学报.2005,32(4),498-504.
[21].Burda,S;Oleszek,W.Antioxident and antiradical activity of flavonoids.Journal of Agriculture and Chemistry.2001,49(6),2774-2779.
[22].Psarra,E;Makris,D.P;Kallithraka,S;et al.Evaluation of the antiradical and reducing properties of selected Greek white wines:correlation with polyphenolic composition.Journal of the science of food and agriculture.2002,82,1014-1020.
[23].Gabrielska,J;Oszmianski,J;Zylka,R;et al.Antioxidant activity of flavones from Scutellaria baicalensis in lecithin liposomes.Zeitschrifl fuer Naturforschung,C:Biosciences.1997,52(11/12),817-823.
[24].赵继红.梁宇.黄酮类化合物抗氧化活性的结构因素.北方工业大学学报.2001,13(1),3644-3652.
[25].吴东方,周本宏,罗顺德.银杏叶黄酮对肝脏 MDA 生成的影响.中国中药杂志.1997,28(6),348-350.
[26].张俊平,王淑英,李小萍,等.水飞蓟对小鼠肝脏炎症损伤和肿瘤坏死因子的产生及活性的影响.药学学报.1996,31(8),577-580.
[27].[25]Shi,Y;Shi,R.B;Liu,B;et al.Studies on antiviral flavonoids in yinqiao san powder.China Journal of Chinese Materia Medica.2001,26(5),321-323.
[28].Wu,J.A;Aattele,A.S;Zhang,L;et al.Anti-HIV activity of medicinal herbs usage and potential development.American Journal of Chinese Medicine.2001,29(1),69-81.
[29].农朝赞,黄华艺,黄酮类化合物抗肿瘤作用的研究应用.中国药房.2004,15(9),568-569.
[30].Musonda,C.A;Chipman,J.K.Quercetin inhibits hydrogrn peroxide-induced NF-kappaB DNA binding activity and DNA damage in Hep G2 ceils.Carcinogenesis.1998,19,1583-1589.
[31].Walker,E.H;Pacokd,M.E;Persic O,et al.Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin,LY294002,quercetin,myricetin and staurosporine.Molecular Cell.2000,6(4),909-919.
[32].Raft,M.M;Rosen,R.T;Vassil,A;et al.Modulation of bcl-2 and cytotoxicity by licochalcone-A,a novel estrogenic flavonoid.Anticancer Research.2000,20(4),2653-2658.
[33].Tron,G.C;Pagliai,F;Del Grosso,E;et al.Synthesis and cytotoxic evaluation of combretafurazans.Journal of Medicinal Chemistry.2005,48,3260-3268.
[34].Kim,Y;Nam,N.H;You,Y.J;et al.Synthesis and cytotoxicity of 3,4-diaryl-2(5H)-furanones.Bioorganic and Medicinal Chemistry Letters.2002,12,719-722.
[35].Wang,L;Woods,K.W;Li,Q;et al.Potent,orally active heterocycle-based combretastatin A-4 analogues:synthesis,structure-activity relationship,pharmacokinetics,and in vitro antitumor activity evaluation.Journal of Medicinal Chemistry.2002,45,1697-1711.
[36].Flynn,B.L;Flynn,G.P;Hamel,E;et al.The synthesis and tubulin binding activity of thiophene-based analogues of combretastatin A-4.Bioorganic and Medicinal Chemistry Letters.2001,11,2341-2343.
[37].Ohsumi,K;Hatananaka,T;Fujita,k;et al.Synthesis and antitumor activity of cis-restricted combretastatins:5-membered heterocyclic analogues.Bioorganic and Medicinal Chemistry Letters.1998,8,3153-3158.
[38].Maya,A.B.S;Perez-Melero,C;Salvador;et al.New naphthylcombretastatins.Modification on the ethylene bridge.Bioorganic & Medicinal Chemistry.2005,13,2097-2107.
[39].Sun,L;Vasilevich,N.I;Fuselier,J.A;et al.Examination of the 1,4-disubstituted azetidinone ring system as a template for combretastatin A-4 conformationally analogue design.Bioorganic Medicinal ChemistryLetters.2004,14,2041-2046.
[40].Jonnalagadda,S.S; ter Haar,E; Hamel,E; et al.Synthesis and biological evaluation of 1,1-dichloro-2,3-diarylcyclopropanes as antitubulin and anti-breast cancer agents.Bioorganic andMedicinal Chemistry.1997,5,715-722.
[41].Hadfield,J.A;Gaukroger,K;Hirst,N;et al.Synthesis and evaluation of double bond substituted combretastatins.European Journal of Medicinal Chemistry.2005,40,529-541.
[42].Ohsumi,K;Nakagawa,R;Fukuda,Y;et al.Novel combretastatin analogues effective against murine solid tumors:design and structure-activity relationships.Journal of Medicinal Chemistry.1998,41,3022-3032.
[43].Giannini,G;Marzi,M;Alloatti,D;et al.GB 2403949,2005.
[44].Cushman,M; Nagarathnam,D; Gopal,D; et al.Synthesis and evaluation of analogues of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents.Journal of Medicinal Chemistry.1992,35,2293-2306.
[45].Lawrence,N.J;Rennison,D;Woo,M;et al.Antimitotic and cell growth inhibitory properties of combretastatin A-4 like ethers.Bioorganic and Medicinal Chemistry Letters.2001,11,51-54.
[46].Gwaltney,S.L.,Ⅱ;Imade,H.M;Barr,K.J;et al.Novel sulfonate analogues of combretastatin A-4:potent antimitotic agents.Bioorganic & Medicinal Chemistry Letters.2001,11,871-874.
[47].Liou,J.P;Chang,Y.L;Kuo,F.M;et al.Concise synthesis and structure-activity relationships of combretastatin A-4 analogues,1-aroylindoles and 3-aroylindoles,as novel classes of potent antitubulin agents.Journal of Medicinal Chemistry.2004,47,4247-4257.
[48].Li,P.K;Xiao,Z;Hu,Z;et al.Conformationally restricted analogs of combretastatin A-4 derived from SU5416.Bioorganic & Medicinal Chemistry Letters.2005,15,5382-5385.
[49].Rizzi,E;Dallavalle,S;Merlini,L;et al.A new synthesis of isoaurones:cytotoxic activity of compounds related to the alleged structure of isoaurostatin.Bioorganic & Medicinal Chemistry Letters.2005,15,4313-4316.
[50].Pettit,G.R;Toki,B;Herald,D.L;et al.Antineoplastic agents.379.Synthesis of phenstatin phosphate.Journal of Medicinal Chemistry.1998,41,1688-1695.
[51].Liou,J.P; Chang,J.Y; Chang,C.W; et al.Synthesis and structure-activity relationships of 3-aminobenzophenones as antimitotic agents.Journal of Medicinal Chemistry.2004,47,2897-2905.
[52].Bailly,C;Bal,C;Barbier,P;et al.Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins.Journal of Medicinal Chemistry.2003,46,5437-5444.
[53].Li,Q;Woods,K.W;Claiborne,A;et al.Synthesis and biological evaluation of 2-indolyloxazolines as a new class of tubulin polymerization inhibitors.Discovery of A-289099 as an orally active antitumor agent.Bioorganic & Medicinal Chemistry Letters.2002,12(3),465-469.
[54].Johnson,M;Younglove,B;Lee,Lauren;et al.Design,synthesis,and biological testing of pyrazoline derivatives of combretastatin A-4.Bioorganic & Medicinal Chemistry Letters.2007,17,5897-5901.
[55].Ducki,S;Forrest,R;Hadfield J.A;et al.Potent antimototic and cell growth inhinitory properties of substituted chalcones.Bioorganic and Medicinal Chemistry.1998,8,1051-1056.
[56].Romagnoli,R;Baraldi,P.G;Jung,M.K.;et al.Synthesis and preliminary biological evaluationof new anti-tubulin agents containing different benzoheterocycles.Bioorganic & Medicinal Chemistry Letters.2005,15,4048-4052.
[57].Flynn,B.L;Hamel,E;Jung,M.K.One-pot synthesis of benzo-[6]furan and indole inhibitors of tubulin polymerization.Journal of Medicinal Chemistry.2002,45,2670-2673.
[58].Xue,N;Yang,X.C;Wu,R;et al.Synthesis and biological evaluation of imidazol-2-one derivatives as potential antitumor agents.Bioorganic and Medicinal Chemistry.2008,16,2550-2557.
[59].Kaffy,J;Pontikis,R;Florent,J.C;et al.Synthesis and biological evaluation of vinylogous combretastatin A-4 derivatives.Organic & Biomolecular Chemistry.2005,3,2657-2660
[60].Kaneda,N;Pezzuto,J.M;Soejarto,D.D;et al.Plant anticancer agents,Ⅺ LⅧ.New cytotoxic flavonoids from Muntingia calabura roots.Journal of Natural Products.1991,54,196-205.
[61].Hori,K;Hashimoto,T;Yokotani,J;et al.Preparation of chromones and medical fungicides containing them.Jpn.Kokai Tokkyo Koho (2001),39 pp.CODEN:JKXXAF JP 2001122868 A 20010508 Patent
[62].Siddaiah,V;Rao,C.V;Venkateswarlu,S;et al.A concise synthesis of polyhydroxydihydrochalcones and homoisofiavonoids.Tetrahedron.2006,62(5),841-846.
[63].Costantino,L;Rastelli,G;Gamberini,M.C;et al.1-Benzopyran-4-one antioxidants as aldose reductase inhibitors.Journal of Medicinal Chemistry.1999,42(11),1881-1893.
[64].Shim,J.S;Kim,J.H;Lee,J;et al.Anti-angiogenic activity of a homoisofiavanone from Cremastra appendiculata.Planta Medica.2004,70,171-173.
[65].Likhitwitayawuid,K;Sawasdee,K;Kirtikara,K.Flavonoids and stilbenoids with COⅩ-1 and COⅩ-2 inhibitory activity from Dracaena loureiri.Planta Medica.2002,68,841-843.
[66].0'Donnell,G;Bucar,F;Gibbons,S.Phytochemistry and antimycobacterial activity of Chlorophytum inornatum.Phytochemistry.2006,67,178-182.
[67].Tsukamoto,S;Wakana,T;Koimaru,K;et al.7-Hydroxy-3-(4-hydroxybenzyl)chroman and broussonin B:Neurotrophic compounds,isolated from Anemarrhena asphodeloides BUNGE,function as proteasome inhibitors.Biological and Pharmaceutical Bulletin.2005,28(9),1798-1800.
[68].Machala,M;Kubinova,R;Horavova,P;et al.Chemoprotective potentials of homoisofiavonoids and chalcones of Dracaena cinnabari:modulations of drug-metabolizing enzymes and antioxidant activity.Phytotherapy Research.2001,15(2),114-118.
[69].Enes,R.F.; Farinha,A.S.F.; Tome,A.C.; et al. Synthesis and antioxidant activity of [60]fullerene-flavonoid conjugates.Tetrahedron.2008,65(1),253-262.
[70].Piazzi,L; Cavalli,A; Belluti,F; et al.Extensive SAR and Computational Studies of 3 - {4-[(Benzylmethylamino)methy l]pheny 1} -6,7-dimethoxy-2H-2-chromenone (AP223 8) Derivatives.Journal of Medicinal Chemistry.2007,50(17),4250-4254.
[71].Rao,Y.K;Rao,C.V;Kishore,P.H;et al.Total synthesis of heliannone A and (R,S)-heliannone B,two bioactive flavonoids from helianthus Cultivars.Journal of Natural Products,2001,64,368-369.
[72].Krauss A.S;Taylor W.C.Intramolecular oxidative coupling of armatic compounds oxidation of siphenolic subtrates.Australian Journal of Chemistry.1991,44(9),1307-1333.
[73].Choi,E.T;Lee,M.H;Kim,Y;et al.Asymmetric dehydration of β-hydroxy esters and application to the syntheses of flavane derivatives.Tetrahedron.2008,64(7),1515-1522.
[74].Bilgic,S;Bilgic,O;Buyukkidan,B;et al.Synthesis of chromans from the reaction of o-quinone methide precursor with substituted styrenes.Journal of Chemical Research.2007,(2),76-79.
[75].Oyama,K;Kondo,T.Total Synthesis of Flavocommelin,a Component of the Blue Supramolecular Pigment from Commelina communis,on the Basis of Direct 6-C-Glycosylation of Flavan.Journal of Organic Chemistry.2004,69(16),5240-5246.
[76].杨金会,李瀛,薛吉军,等.黄烷类化合物研究(Ⅱ)－(±)－4'－羟基－5,7,3'－三甲氧基黄烷和(±)－5,4'－二羟基-7,3'－二甲氧基黄烷的全合成.高等学校化学学报.2002,23(2),234-237.
[77].Nussbaumer,P;Lehr,P;Billich,A.2-Substituted 4-(Thio)chromenone 6-O-Sulfamates:Potent Inhibitors of Human Steroid Sulfatase.Journal of Medicinal Chemistry.2002,45(19),4310-4320.
[78].程永浩,段亚波,戚燕,等.松属素的均匀优化设计法合成研究.化学研究与应用,2006,18(11),1334-1335.
[79].Levai,A.Epoxidation of homoisoflavones.Joumal of Heterocyclic Chemistry.2003,40(2),395-397.
[80].Adam,W;Halasz,J;Levai,A;et al.Dimethyldioxirane oxidation of 3-arylidenechromanones.Liebigs Annalen der Chemic.1994,(8),795-803.
[81].Eiden,F;Schuenemann,J.Synthesis and reactions of 6-acylkhellin derivatives.Archiv der Pharmazie.1983,316(3),201-209.
[82].Cavalli,A;Bisi,A;Bertucci,C;et al.Enantioselective Nonsteroidal Aromatase Inhibitors Identified through a Multidisciplinary Medicinal Chemistry Approach.Journal of Medicinal Chemistry.2005,48(23),7282-7289.
[83].Vaisburg,A;Paquin,I;Bernstein,N;et al.N-(2-Amino-phenyl)-4-(heteroarylmethyl)-benzamides as new histone deacetylase inhibitors.Bioorganic & Medicinal Chemistry Letters.2007,17(24),6729-6733.
[84].Kirkiacharian,S;Tongo,H.G.;Bastide,J;et al.Synthesis and angioprotective,antiallergic and antihistaminic activities of 3-benzylchromones(homoisoflavones).European Journal of Medicinal Chemistry.1989,24(5),541-546.
[85].Siddaiah,V;Rao,C.V;Venkateswarlu,S;et al.A concise synthesis of polyhydroxydihydrochalcones and homoisoflavonoids.Tetrahedron.2006,62(5),841-846.
[86].Kirkiacharian,B.S;Gomis,M.New convenient synthesis of homoisoflavanones and (±)-di-O-methyldihydroeucomin.Synthetic Communications.2005,35(4),563-569.
[87].Orjala,J;Wright,A.D;Behrends,H;et al.Cytotoxic and antibacterial dihydrochalcones from piper aduncum.Journal of Natural Products.1994,57(1),18-26.
[88].Cheenpracha,S;Kamlai,C;Ponglimanont,C;et al.Anti-HIV-1 protease activity of compounds from Boesenbergia pandurata.Bioorganic and Medecinal Chemistry.2006,14(6),1710-1714.
[89].Hermoso,A:Jiménez,I.A;Mamani,Z.A;et al.Antileishmanial activities of dihydrochalcones from piper elongatum and synthetic related compounds.Structural requirements for activity.Bioorganic and Medicinal Chemistry.2003,11(18),3975-3980.
[90].Besong,G; Jarowicki,K; Kocienski,P.J.; et al.Synthesis of (S)-(-)-N-acetylcolchinol using intramolecular biaryl oxidative coupling.Organic & Biomolecular Chemistry.2006,4(11),2193-2207.
[91].Salvador JAR,Melo MLS,Neves ASC.Ultrasound Assisted Zinc Reactions in Synthesis 2.A New Clemmensen-type Reduction.Tetrahedron Letters.1993,34:361-362
[92].Bentley,J;Nilsson,P.A.;Parsons,A.F.Tributyltin hydride-mediated radical cyclization of carbonyls to form functionalized oxygen and nitrogen heterocycles.Journal of the Chemical Society,Perkin Transactions 1.2002,(12),1461-1469.
[93].Koch,K; Smitrovich,J H.Hydroxy-directed hydroaluminations:a stereoselective approach to cycloalkanols from β-aryl enones.Tetrahedron Letters.1994,35(8),1137-1140.
[94].Gomis,M;Kirkiacharian,B.S.Hydride reduction and hydroboration study of the stereoselectivity of a new approach to 3-(arylmethyl)-4-chromanols (homoisoflavanols).Tetrahedron.1990,46(6),1849-1858.
[95].Jones,B;Schildknegt,K;Wright,K;et al.The synthesis of an aminohexyl-containing analog of the chromanol leukotriene b4 receptor antagonist CP-195543:A scaffold for the preparation of derivatized analogs.Heterocycles.53(8),1713-1724.
[96].Gomis,M;Kirkiacharian,B.S;Likforman,J;et al.Reduction by hydrides.Synthesis and stereochemistry of 3-benzyl-4-chromanols.Bulletin de la Societe Chimique de France.1988,(3),585-590.
[97].Blasko,G;Cordell,G.A.Biomimetic total synthesis of dracaenone derivatives.Heterocycles.1988,27(2),445-452.
[98].Usse,S;Guillaumet,G;Viaud,M-C.A new route to 3,4-dihydro-2H-l-benzopyrans substituted at 3-position via palladium-catalyzed reactions.Tetrahedron Letters.1997,38(31),5501-5502.
[2].蔡仲曦,林华.我国抗肿瘤药物调查与分析.中国新药杂志.2001,10(3),233-236.
[3].陆江海,李秀兰,刘沁率,赵玉英.天然产物与药物的发现.国外医药·植物药分册.2000,15(2),47-79.
[4].Wani,M.C.;Taylor,H.L.;Wall,M.E.;et al.Plant antitumor agents.Ⅳ.Isolation and structure of taxol,a novel antileukemic and antitumor agent from Taxus brevifolia.Journal of the American Chemical Society.1971,93(9),2325-2327.
[5].莫晓媚,李静,耿美玉.DNA 拓扑异构酶与抗肿瘤.中国药理学通报.2007,23(1),20-23。
[6].Wall,M.E;Wani,M.C;Cook,C.E;et al.Antitumor agent I.The isolation and structure of Camptothecin,a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate.Journal of American Chemical Society.1966,88(16),3888-3890.
[7].潘显道,王存英.天然抗肿瘤药喜树碱衍生物的研究进展.药学学报.2003,38(9),715-720.
[8].郭仕华,娄红祥,贺艳丽.天然抗肿瘤药物的研究进展.国外医药.植物药分册.2005,20(5),190-196.
[9].Takaoka,M.Phenolic substance of white hellebore(Veratrum grandiflorum Loes fil.).Ⅲ.Constitution of resveratrol.Nippon Kagaku Kaishi.(1921-1947).1940,61,30-4.
[10].Tseng,S.H;Lin,S.M;Chen,J.C;et al.Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats.Clinical Cancer Research.2004,10(6),2190-2202.
[11].Lin,M.T;Yen,M.L;Lin,C.Y;et al.Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation.Molecular Pharmacology.2003,64(5),1029-1036.
[12].Pettit,G.R;Singh,S.B;Hamel,E;et al.Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4.Experientia.1989,45,209-211.
[13].Kanthou,C;Tozer,G.M.The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells.Blood.2002,99(6),2060-2069.
[14].Kador,P.F;Blessing K;Randazzo J;et al.Evaluation of the vascular targeting agent combretastatin a-4prodrug on retinal neovascularization in the galactose-fed dog.Journal of ocular pharmacology and therapeutics:the official journal of the Association for Ocular Pharmacology and Therapeutics.2007,23(2),132-142.
[15].Pinney,K.G;Jelinek,C;Evardsen,K;et al.The discovery and development of the combretastatins.In Anticancer Agents from Natural Products;Cragg GM,Kingston DGI,Newman D J,Eds.;Brunner-Routledge Psychology Press,Taylor & Francis Group:Boca Raton,FL,2005;pp 23-46.
[16].Brooks,A.C;Kanthou,C;Cook,I.H;et al.The vascular targeting agent combretastatin A-4-phosphate induces neutrophil recruitment to endothelial cells in vitro.Anticancer Research 2003,23,3199-3206.
[17].Siemann,D.W.;Shi,W.Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors.International Journal of Radiation Oncology,Biology,Physics.2004,60(4),1233-1240.
[18].许旭东,胡晓茹,杨峻山.抗肿瘤药用植物有效成分研究概况.中国中药杂志.2008,33,2079-2081.
[19].李云霞,贺文智,索全伶,等.黄酮类化合物活性及构效关系研究概况.内蒙古石油化工.2004,30(2),10-12.
[20].方从兵,宛晓春,江昌俊.黄酮类化合物生物合成的研究进展.安徽农业大学学报.2005,32(4),498-504.
[21].Burda,S;Oleszek,W.Antioxident and antiradical activity of flavonoids.Journal of Agriculture and Chemistry.2001,49(6),2774-2779.
[22].Psarra,E;Makris,D.P;Kallithraka,S;et al.Evaluation of the antiradical and reducing properties of selected Greek white wines:correlation with polyphenolic composition.Journal of the science of food and agriculture.2002,82,1014-1020.
[23].Gabrielska,J;Oszmianski,J;Zylka,R;et al.Antioxidant activity of flavones from Scutellaria baicalensis in lecithin liposomes.Zeitschrifl fuer Naturforschung,C:Biosciences.1997,52(11/12),817-823.
[24].赵继红.梁宇.黄酮类化合物抗氧化活性的结构因素.北方工业大学学报.2001,13(1),3644-3652.
[25].吴东方,周本宏,罗顺德.银杏叶黄酮对肝脏 MDA 生成的影响.中国中药杂志.1997,28(6),348-350.
[26].张俊平,王淑英,李小萍,等.水飞蓟对小鼠肝脏炎症损伤和肿瘤坏死因子的产生及活性的影响.药学学报.1996,31(8),577-580.
[27].[25]Shi,Y;Shi,R.B;Liu,B;et al.Studies on antiviral flavonoids in yinqiao san powder.China Journal of Chinese Materia Medica.2001,26(5),321-323.
[28].Wu,J.A;Aattele,A.S;Zhang,L;et al.Anti-HIV activity of medicinal herbs usage and potential development.American Journal of Chinese Medicine.2001,29(1),69-81.
[29].农朝赞,黄华艺,黄酮类化合物抗肿瘤作用的研究应用.中国药房.2004,15(9),568-569.
[30].Musonda,C.A;Chipman,J.K.Quercetin inhibits hydrogrn peroxide-induced NF-kappaB DNA binding activity and DNA damage in Hep G2 ceils.Carcinogenesis.1998,19,1583-1589.
[31].Walker,E.H;Pacokd,M.E;Persic O,et al.Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin,LY294002,quercetin,myricetin and staurosporine.Molecular Cell.2000,6(4),909-919.
[32].Raft,M.M;Rosen,R.T;Vassil,A;et al.Modulation of bcl-2 and cytotoxicity by licochalcone-A,a novel estrogenic flavonoid.Anticancer Research.2000,20(4),2653-2658.
[33].Tron,G.C;Pagliai,F;Del Grosso,E;et al.Synthesis and cytotoxic evaluation of combretafurazans.Journal of Medicinal Chemistry.2005,48,3260-3268.
[34].Kim,Y;Nam,N.H;You,Y.J;et al.Synthesis and cytotoxicity of 3,4-diaryl-2(5H)-furanones.Bioorganic and Medicinal Chemistry Letters.2002,12,719-722.
[35].Wang,L;Woods,K.W;Li,Q;et al.Potent,orally active heterocycle-based combretastatin A-4 analogues:synthesis,structure-activity relationship,pharmacokinetics,and in vitro antitumor activity evaluation.Journal of Medicinal Chemistry.2002,45,1697-1711.
[36].Flynn,B.L;Flynn,G.P;Hamel,E;et al.The synthesis and tubulin binding activity of thiophene-based analogues of combretastatin A-4.Bioorganic and Medicinal Chemistry Letters.2001,11,2341-2343.
[37].Ohsumi,K;Hatananaka,T;Fujita,k;et al.Synthesis and antitumor activity of cis-restricted combretastatins:5-membered heterocyclic analogues.Bioorganic and Medicinal Chemistry Letters.1998,8,3153-3158.
[38].Maya,A.B.S;Perez-Melero,C;Salvador;et al.New naphthylcombretastatins.Modification on the ethylene bridge.Bioorganic & Medicinal Chemistry.2005,13,2097-2107.
[39].Sun,L;Vasilevich,N.I;Fuselier,J.A;et al.Examination of the 1,4-disubstituted azetidinone ring system as a template for combretastatin A-4 conformationally analogue design.Bioorganic Medicinal ChemistryLetters.2004,14,2041-2046.
[40].Jonnalagadda,S.S; ter Haar,E; Hamel,E; et al.Synthesis and biological evaluation of 1,1-dichloro-2,3-diarylcyclopropanes as antitubulin and anti-breast cancer agents.Bioorganic andMedicinal Chemistry.1997,5,715-722.
[41].Hadfield,J.A;Gaukroger,K;Hirst,N;et al.Synthesis and evaluation of double bond substituted combretastatins.European Journal of Medicinal Chemistry.2005,40,529-541.
[42].Ohsumi,K;Nakagawa,R;Fukuda,Y;et al.Novel combretastatin analogues effective against murine solid tumors:design and structure-activity relationships.Journal of Medicinal Chemistry.1998,41,3022-3032.
[43].Giannini,G;Marzi,M;Alloatti,D;et al.GB 2403949,2005.
[44].Cushman,M; Nagarathnam,D; Gopal,D; et al.Synthesis and evaluation of analogues of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents.Journal of Medicinal Chemistry.1992,35,2293-2306.
[45].Lawrence,N.J;Rennison,D;Woo,M;et al.Antimitotic and cell growth inhibitory properties of combretastatin A-4 like ethers.Bioorganic and Medicinal Chemistry Letters.2001,11,51-54.
[46].Gwaltney,S.L.,Ⅱ;Imade,H.M;Barr,K.J;et al.Novel sulfonate analogues of combretastatin A-4:potent antimitotic agents.Bioorganic & Medicinal Chemistry Letters.2001,11,871-874.
[47].Liou,J.P;Chang,Y.L;Kuo,F.M;et al.Concise synthesis and structure-activity relationships of combretastatin A-4 analogues,1-aroylindoles and 3-aroylindoles,as novel classes of potent antitubulin agents.Journal of Medicinal Chemistry.2004,47,4247-4257.
[48].Li,P.K;Xiao,Z;Hu,Z;et al.Conformationally restricted analogs of combretastatin A-4 derived from SU5416.Bioorganic & Medicinal Chemistry Letters.2005,15,5382-5385.
[49].Rizzi,E;Dallavalle,S;Merlini,L;et al.A new synthesis of isoaurones:cytotoxic activity of compounds related to the alleged structure of isoaurostatin.Bioorganic & Medicinal Chemistry Letters.2005,15,4313-4316.
[50].Pettit,G.R;Toki,B;Herald,D.L;et al.Antineoplastic agents.379.Synthesis of phenstatin phosphate.Journal of Medicinal Chemistry.1998,41,1688-1695.
[51].Liou,J.P; Chang,J.Y; Chang,C.W; et al.Synthesis and structure-activity relationships of 3-aminobenzophenones as antimitotic agents.Journal of Medicinal Chemistry.2004,47,2897-2905.
[52].Bailly,C;Bal,C;Barbier,P;et al.Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins.Journal of Medicinal Chemistry.2003,46,5437-5444.
[53].Li,Q;Woods,K.W;Claiborne,A;et al.Synthesis and biological evaluation of 2-indolyloxazolines as a new class of tubulin polymerization inhibitors.Discovery of A-289099 as an orally active antitumor agent.Bioorganic & Medicinal Chemistry Letters.2002,12(3),465-469.
[54].Johnson,M;Younglove,B;Lee,Lauren;et al.Design,synthesis,and biological testing of pyrazoline derivatives of combretastatin A-4.Bioorganic & Medicinal Chemistry Letters.2007,17,5897-5901.
[55].Ducki,S;Forrest,R;Hadfield J.A;et al.Potent antimototic and cell growth inhinitory properties of substituted chalcones.Bioorganic and Medicinal Chemistry.1998,8,1051-1056.
[56].Romagnoli,R;Baraldi,P.G;Jung,M.K.;et al.Synthesis and preliminary biological evaluationof new anti-tubulin agents containing different benzoheterocycles.Bioorganic & Medicinal Chemistry Letters.2005,15,4048-4052.
[57].Flynn,B.L;Hamel,E;Jung,M.K.One-pot synthesis of benzo-[6]furan and indole inhibitors of tubulin polymerization.Journal of Medicinal Chemistry.2002,45,2670-2673.
[58].Xue,N;Yang,X.C;Wu,R;et al.Synthesis and biological evaluation of imidazol-2-one derivatives as potential antitumor agents.Bioorganic and Medicinal Chemistry.2008,16,2550-2557.
[59].Kaffy,J;Pontikis,R;Florent,J.C;et al.Synthesis and biological evaluation of vinylogous combretastatin A-4 derivatives.Organic & Biomolecular Chemistry.2005,3,2657-2660
[60].Kaneda,N;Pezzuto,J.M;Soejarto,D.D;et al.Plant anticancer agents,Ⅺ LⅧ.New cytotoxic flavonoids from Muntingia calabura roots.Journal of Natural Products.1991,54,196-205.
[61].Hori,K;Hashimoto,T;Yokotani,J;et al.Preparation of chromones and medical fungicides containing them.Jpn.Kokai Tokkyo Koho (2001),39 pp.CODEN:JKXXAF JP 2001122868 A 20010508 Patent
[62].Siddaiah,V;Rao,C.V;Venkateswarlu,S;et al.A concise synthesis of polyhydroxydihydrochalcones and homoisofiavonoids.Tetrahedron.2006,62(5),841-846.
[63].Costantino,L;Rastelli,G;Gamberini,M.C;et al.1-Benzopyran-4-one antioxidants as aldose reductase inhibitors.Journal of Medicinal Chemistry.1999,42(11),1881-1893.
[64].Shim,J.S;Kim,J.H;Lee,J;et al.Anti-angiogenic activity of a homoisofiavanone from Cremastra appendiculata.Planta Medica.2004,70,171-173.
[65].Likhitwitayawuid,K;Sawasdee,K;Kirtikara,K.Flavonoids and stilbenoids with COⅩ-1 and COⅩ-2 inhibitory activity from Dracaena loureiri.Planta Medica.2002,68,841-843.
[66].0'Donnell,G;Bucar,F;Gibbons,S.Phytochemistry and antimycobacterial activity of Chlorophytum inornatum.Phytochemistry.2006,67,178-182.
[67].Tsukamoto,S;Wakana,T;Koimaru,K;et al.7-Hydroxy-3-(4-hydroxybenzyl)chroman and broussonin B:Neurotrophic compounds,isolated from Anemarrhena asphodeloides BUNGE,function as proteasome inhibitors.Biological and Pharmaceutical Bulletin.2005,28(9),1798-1800.
[68].Machala,M;Kubinova,R;Horavova,P;et al.Chemoprotective potentials of homoisofiavonoids and chalcones of Dracaena cinnabari:modulations of drug-metabolizing enzymes and antioxidant activity.Phytotherapy Research.2001,15(2),114-118.
[69].Enes,R.F.; Farinha,A.S.F.; Tome,A.C.; et al. Synthesis and antioxidant activity of [60]fullerene-flavonoid conjugates.Tetrahedron.2008,65(1),253-262.
[70].Piazzi,L; Cavalli,A; Belluti,F; et al.Extensive SAR and Computational Studies of 3 - {4-[(Benzylmethylamino)methy l]pheny 1} -6,7-dimethoxy-2H-2-chromenone (AP223 8) Derivatives.Journal of Medicinal Chemistry.2007,50(17),4250-4254.
[71].Rao,Y.K;Rao,C.V;Kishore,P.H;et al.Total synthesis of heliannone A and (R,S)-heliannone B,two bioactive flavonoids from helianthus Cultivars.Journal of Natural Products,2001,64,368-369.
[72].Krauss A.S;Taylor W.C.Intramolecular oxidative coupling of armatic compounds oxidation of siphenolic subtrates.Australian Journal of Chemistry.1991,44(9),1307-1333.
[73].Choi,E.T;Lee,M.H;Kim,Y;et al.Asymmetric dehydration of β-hydroxy esters and application to the syntheses of flavane derivatives.Tetrahedron.2008,64(7),1515-1522.
[74].Bilgic,S;Bilgic,O;Buyukkidan,B;et al.Synthesis of chromans from the reaction of o-quinone methide precursor with substituted styrenes.Journal of Chemical Research.2007,(2),76-79.
[75].Oyama,K;Kondo,T.Total Synthesis of Flavocommelin,a Component of the Blue Supramolecular Pigment from Commelina communis,on the Basis of Direct 6-C-Glycosylation of Flavan.Journal of Organic Chemistry.2004,69(16),5240-5246.
[76].杨金会,李瀛,薛吉军,等.黄烷类化合物研究(Ⅱ)－(±)－4'－羟基－5,7,3'－三甲氧基黄烷和(±)－5,4'－二羟基-7,3'－二甲氧基黄烷的全合成.高等学校化学学报.2002,23(2),234-237.
[77].Nussbaumer,P;Lehr,P;Billich,A.2-Substituted 4-(Thio)chromenone 6-O-Sulfamates:Potent Inhibitors of Human Steroid Sulfatase.Journal of Medicinal Chemistry.2002,45(19),4310-4320.
[78].程永浩,段亚波,戚燕,等.松属素的均匀优化设计法合成研究.化学研究与应用,2006,18(11),1334-1335.
[79].Levai,A.Epoxidation of homoisoflavones.Joumal of Heterocyclic Chemistry.2003,40(2),395-397.
[80].Adam,W;Halasz,J;Levai,A;et al.Dimethyldioxirane oxidation of 3-arylidenechromanones.Liebigs Annalen der Chemic.1994,(8),795-803.
[81].Eiden,F;Schuenemann,J.Synthesis and reactions of 6-acylkhellin derivatives.Archiv der Pharmazie.1983,316(3),201-209.
[82].Cavalli,A;Bisi,A;Bertucci,C;et al.Enantioselective Nonsteroidal Aromatase Inhibitors Identified through a Multidisciplinary Medicinal Chemistry Approach.Journal of Medicinal Chemistry.2005,48(23),7282-7289.
[83].Vaisburg,A;Paquin,I;Bernstein,N;et al.N-(2-Amino-phenyl)-4-(heteroarylmethyl)-benzamides as new histone deacetylase inhibitors.Bioorganic & Medicinal Chemistry Letters.2007,17(24),6729-6733.
[84].Kirkiacharian,S;Tongo,H.G.;Bastide,J;et al.Synthesis and angioprotective,antiallergic and antihistaminic activities of 3-benzylchromones(homoisoflavones).European Journal of Medicinal Chemistry.1989,24(5),541-546.
[85].Siddaiah,V;Rao,C.V;Venkateswarlu,S;et al.A concise synthesis of polyhydroxydihydrochalcones and homoisoflavonoids.Tetrahedron.2006,62(5),841-846.
[86].Kirkiacharian,B.S;Gomis,M.New convenient synthesis of homoisoflavanones and (±)-di-O-methyldihydroeucomin.Synthetic Communications.2005,35(4),563-569.
[87].Orjala,J;Wright,A.D;Behrends,H;et al.Cytotoxic and antibacterial dihydrochalcones from piper aduncum.Journal of Natural Products.1994,57(1),18-26.
[88].Cheenpracha,S;Kamlai,C;Ponglimanont,C;et al.Anti-HIV-1 protease activity of compounds from Boesenbergia pandurata.Bioorganic and Medecinal Chemistry.2006,14(6),1710-1714.
[89].Hermoso,A:Jiménez,I.A;Mamani,Z.A;et al.Antileishmanial activities of dihydrochalcones from piper elongatum and synthetic related compounds.Structural requirements for activity.Bioorganic and Medicinal Chemistry.2003,11(18),3975-3980.
[90].Besong,G; Jarowicki,K; Kocienski,P.J.; et al.Synthesis of (S)-(-)-N-acetylcolchinol using intramolecular biaryl oxidative coupling.Organic & Biomolecular Chemistry.2006,4(11),2193-2207.
[91].Salvador JAR,Melo MLS,Neves ASC.Ultrasound Assisted Zinc Reactions in Synthesis 2.A New Clemmensen-type Reduction.Tetrahedron Letters.1993,34:361-362
[92].Bentley,J;Nilsson,P.A.;Parsons,A.F.Tributyltin hydride-mediated radical cyclization of carbonyls to form functionalized oxygen and nitrogen heterocycles.Journal of the Chemical Society,Perkin Transactions 1.2002,(12),1461-1469.
[93].Koch,K; Smitrovich,J H.Hydroxy-directed hydroaluminations:a stereoselective approach to cycloalkanols from β-aryl enones.Tetrahedron Letters.1994,35(8),1137-1140.
[94].Gomis,M;Kirkiacharian,B.S.Hydride reduction and hydroboration study of the stereoselectivity of a new approach to 3-(arylmethyl)-4-chromanols (homoisoflavanols).Tetrahedron.1990,46(6),1849-1858.
[95].Jones,B;Schildknegt,K;Wright,K;et al.The synthesis of an aminohexyl-containing analog of the chromanol leukotriene b4 receptor antagonist CP-195543:A scaffold for the preparation of derivatized analogs.Heterocycles.53(8),1713-1724.
[96].Gomis,M;Kirkiacharian,B.S;Likforman,J;et al.Reduction by hydrides.Synthesis and stereochemistry of 3-benzyl-4-chromanols.Bulletin de la Societe Chimique de France.1988,(3),585-590.
[97].Blasko,G;Cordell,G.A.Biomimetic total synthesis of dracaenone derivatives.Heterocycles.1988,27(2),445-452.
[98].Usse,S;Guillaumet,G;Viaud,M-C.A new route to 3,4-dihydro-2H-l-benzopyrans substituted at 3-position via palladium-catalyzed reactions.Tetrahedron Letters.1997,38(31),5501-5502.