新结构HIV及VEGF抑制剂的研究
摘要
本论文研究进行了HIV抑制剂和VEGF抑制剂二方面的工作:
(一) DCK类似物的设计、合成和HIV抑制活性研究
Suksdorfin(1)是美国北卡大学药学院K.H.Lee课题组从植物LomatiumSuksdorfii的果实中分离而得的双氧杂三环稠杂环化合物,具有明显抗HIV活性(EC_(50)=2.6±2.1μM,TI=30.6±22.4,TI=therapeutic index IC_(50)/EC_(50))。Lee小组以此化合物为先导,进行了一系列的结构修饰和生物活性观察,先后获得DCK(2)(EC_(50)4×10~_(-4)μM,TI=136719)和4-甲基-DCK(11)(EC_(50)=1.57×10~(-7)μM,TI＞10~9)等化合物,其极低的EC_(50)值和极高的TI值引起了极为广泛的关注。
最近的药理作用机理研究表明,HIV-1逆转录酶可能是DCK类化合物的作用靶点,DCK类化合物不明显抑制依赖RNA的DNA合成,而对依赖DNA的DNA聚合酶的活性具有强的抑制作用,其体外测定的高活性和选择性以及独特药理作用位点,使得DCK类化合物成为非常有潜力的新结构类型抗HIV药物研究领域。因此,对DCK类化合物进一步的化学修饰和结构改造研究,进而揭示其结构与活性之间的关系,一方面可以为寻求活性更好的先导化合物提供信息和线索,同时可以探测与之相结合的作用靶点生物大分子的模型和结构信息,对研究这类化合物的分子药理作用机制具有重要的学术意义。
近年来,本课题组相继完成了用N,N-,O,N-,N,O-,O,S-,S,O-及O,C-分别代替DCK类化合物中A环或C环原有的氧原子而形成的三环稠杂环衍生物的合成及生物活性测试,其中1-thio-DCK(22a)、7-thio-DCK(21a)和4-甲基-DCK的内酰胺类似物(17a)(N,O-杂)均显示出优异的抗HIV活性;7-carbon-DCK(24b,25)的活性有一定程度下降,说明在DCK的7-位可能与靶点间存在电效应。
在这些结果的基础上,我们进一步开展了针对DCK类化合物A环结构骨架的化学修饰工作。设计了保留化合物(23a)中的1-位S原子,将4-位C原子替换成N原子的1,4-噻嗪-2-酮结构(26)及其异构体1,4-噻嗪-3-酮结构(27)和相应的类似物(28),进行合成和生物活性探索。这些目标化合物均属结构新颖的杂环体系,在化学合成上存在着一定的难度和挑战性,因此本工作对该类杂环化合物合成方法的探索和发展具有一定的学术意义。
根据逆合成分析法,以对甲氧基苯胺为起始原料,分别经过两条合成路线,成功合成了目标化合物的关键三环结构前体化合物(36,39)。在构键9,10-位羟基的时候,发现上述三类A环结构的改变,使9,10-位双键不能顺利发生Sharpless双羟化反应,因而未能完成含9,10-双樟脑酸酯的目标化合物。但通过环氧化、及溴羟化反应的探索,得到了10-位单羟基的前体,并进一步樟脑酰化合成了10-单樟脑酸酯DCK类似物(144)送活性测试。
2004年Lee课题组报道了对A环进行结构改造的DCK类化合物的新进展,即将α-吡喃酮环替代为γ-吡喃酮环(DCP 69,70),结果表明化合物70也具有相当的活性(EC_(50)=0.00032μM,TI=116200)。这一结果证明了对DCK的香豆素型A环的结构改造,是有探索前景和值得进一步研究的。
结合DCP类化合物的研究成果和前期研究对DCK类化合物结构修饰过程中积累的对构效关系认识和信息,为了探索A环和C环完整性对活性的影响,进行了Seco-DCK类新结构类似物的设计和合成研究。通过断裂A环和C环的不同碳链位置来剖析结构,寻找最简洁的有效骨架单元和必要药效团,为进一步阐明构效关系提供有用的信息。成功地合成了以下四个系列的Seco-DCK类似物:
Seco-DCK类似物是DCK系列抗HIV药物研究中一个结构上的新突破,部分目标化合物的初步活性结果显示具有显著的抗HIV活性,是一类未见文献报道的新结构类型的HIV抑制剂。其中,化合物74表现出良好的抗HIV活性(IC_(50)＞25μg/mL(58.4μM),EC_(50)＜0.025μg/mL(0.058 gM),TI＞1000),化合物71b表现出一定的抗HIV活性(IC_(50)＞25μg/mL(39.04μM),EC_(50)＜0.12μg/mL(0.19μM),TI＞208),化合物73和75则表现出稍弱的抗HIV活性(IC_(50)＞25μg/mL(39.2μM),EC_(50)=16.2μg/mL(25.4μM),TI=1.7;IC_(50)=＞25μg/mL(56.5μM),EC_(50)=15.8μg/mL(35.7μM),TI=1.83),化合物72则完全失去了活性。部分目标化合物的最终精确活性数据尚在测定中。通过比较,可以得出以下一些DCK类衍生物抗HIV构效关系及与其相作用的生物靶分子结构的新信息和新认识:
(1) 4-Me-DCK的A环C_2-C_3位开环后的类似物71b仍保持了一定的的抗HIV活性,说明对A环完整性是否有必要值得深入研究,揭示了A环开环类似物的研究,具有进一步修饰的空间。A环部分与受体的结合是通过氢键、电效应还是空间上的嵌合可通过对A环开环类似物的深入研究得以进一步阐明,从而为设计合成和寻找新结构类型的抗HIV药物提供新的线索。
(2)化合物72活性的消失说明可能由于两个樟脑酰基药效团的优势构象在空间上远离了原来DCK类的9,10-位靶点结合区域,以致活性的消失。从而证明了樟脑酰基药效团应该保留在香豆素环8-位取代基上。
(3)化合物73和75仅保留了较弱的活性,揭示了受体在与DCK类化合物9,10-位樟脑酸酯结合的位点,在α-面仅存在一个非常狭小的空穴。10-位樟脑酸酯处于分子β-面与受体靶点相结合,其10-位α-面的H改变为-CH3后活性显著下降,α-面更大的基团将导致活性的大幅度下降.此点与DCK类化合物中两个樟脑酸酯基严格的构型要求的经验相一致。
(4)化合物74保留了较强的活性,说明DCK中10-位的樟脑酰基是必要基团,而9-位的樟脑酰基对药效的影响并非十分重要;C环的完整性也不是绝对必要的;而且这类C环Seco-DCK化合物的分子量大大减小、药物设计软件显示log P值、溶解度和生物利用度都有可能好于4-Me-DCK,同时也避免了4-Me-DCK类化合物中由于两个空间拥挤邻位顺式樟脑酯大基团的存在而造成代谢不稳定的影响。此外,由于结构的简化,特别是去除了分子中的手性要求,在合成上大大简化了难度,有利于成药性的提高。这些初步研究结果,为新一类HIV抑制剂的深入研究提供了线索,打下了重要基础。
我们还以化合物74为hit设计合成了一系列类似物(110-117),待活性结果返回后可以提供更详细的信息。
另外,化合物71b在HCV的活性筛选中表现出了一定的活性,为今后的研究提供了一个新的先导化合物,我们可以以其为hit进行设计研究,丰富和扩展我们的抗病毒药物研究内容。
在合成中遇到的一些化学反应意外行为进行了较细致的研究,分别鉴定了产物的结构并解释了异常产物形成的原因,对该类化合物的合成方法和化学性质提供了新知。
(二)苯并噻唑啉衍生物的设计、合成和VEGF抑制活性研究
1.以邻甲氨基苯硫酚和各种醛、酮化合物缩合合成的2-取代苯并噻唑啉化合物
(2)及其衍生物(3,4)在VEGF的活性筛选中均表现出一定程度的抑制作用;其中个别化合物表现出了较好的活性水平(2b(EC_(50)=0.07 mM,SI=25);21(EC_(50)=0.115 mM,SI＞32);3g(EC_(50)=0.03 mM,SI＞32);4b(EC_(50)＜0.15mM,SI＞32));该类化合物的VEGF抑制作用未见文献报道,为新结构VEGF抑制剂的寻找和发现提供了新的信息。
2.发现了2-位单取代苯并噻唑啉化合物普遍存在的自发游离基氧化偶联反应现象,并对影响该反应的因素进行了细微深入的研究:在大多数有机溶剂中均会自发发生氧化偶联反应生成相应的二硫化合物;在醇类溶剂或有少量酸存在的的情况下则会抑制该类反应的发生;这类化合物发生的速率与2-位苯环上的取代基有关:温度可以显著提高该类化合物反应速率和转化率。对反应过程中得到的多种意外产物确证了结构,丰富了该类杂环化合物化学的新认识。
3.对采用苯并噻唑啉作为羰基保护基和脱保护的方法进行了拓展研究。在对课题组发现的pTS/vinyl ether脱保护法扩展底物的研究中发现:对于由芳醛形成的噻唑啉底物该方法过于剧烈,会将底物破坏,产生复杂的聚合物;而和某些2-单芳基取代噻唑啉化合物反应时会定量生成季胺盐。由酮形成的噻唑啉,即2-位双取代的噻唑啉底物可用浓盐酸脱保护,对于2-位单取代的噻唑啉底物则盐酸的存在可以抑制其氧化偶联游离基反应的发生,过量的浓盐酸会生成相应的噻唑季胺盐.此外,还发现了CH_3UTHF/H_2O体系也可进行该类化合物的脱保护。不同脱保护试剂的研究以及在脱保护反应中选择性行为,为在有机合成上的应用提供了新的线索。
上述两部分研究共合成化合物180个,其中90余个是未见文献报道的新化合物,均经波谱测定确证结构。
This dissertation has two parts of research as followed:
Design,Synthesis of DCK Analogs and HIV Inhibitory Activity:
Suksdorfin(1),a natural product isolated from the fruit of Lomatium Suksdorfii, has an angular pyranocoumarin skeleton with interesting biological properties, especially its anti-HIV activity(EC_(50)=2.6±2.1μM,TI=30.6±22.4,TI= therapeutic index IC_(50)/EC_(50)).Structural modification of 1 yielded DCK(2) and 4-methyl-DCK(11),which demonstrated extremely potent inhibitory activity against HIV-1 replication in H9 lymphocytic cells(EC_(50)=4×10~(-4)μM,TI=136719 and EC_(50) =1.57×10~(-7)μM,TI＞10~9,respectively).
The recent mechanistic studies indicated that HIV-1 RT is possibly the target of DCK and DCK is a unique HIV-1 RT inhibitor that inhibits the DNA-dependent DNA polymerase activity.In contrast,DCK did not significantly affect the RNA-dependent DNA polymerase activity.Due to its unique mode of action,DCK and its derivatives with high activity and selectivity become an attactive new anti-HIV drug research field.Accordingly,selected modifications on DCK skeleton are highly desirable in order to identify the pharmacophores in this class of potent anti-HIV agents and explore the structural aspect of the target bio-molecule(s).To this end,a variety of novel DCK analogs containing N,N-,O,N-,N,O-,O,S-,S,O- or O,C- by displacing the O,O atoms in the DCK skeleton were synthesized previously in our group.The structural modifications of 4-methyl-DCK by replacing the ring oxygen atom of DCK with a sulfur or a nitrogen atom(22a,23a and 17a) demonstrated that these analogs also exhibited potent inhibitory effects on HIV-1 replication in H9 lymphocytes;some O,C- analogs(24b,25) which showed lower inhibitory effects implied that there probably was a electronic effect at 7-position with the target.
On the basis of these results,we have expanded further structural modification aiming at the A ring of DCK.Keeping the S atom at the 1-position of compound(23a) and replacing the C to N atom at the 4-position,we designed,synthesized and bioactively explored 1,4-thiazine-2-one structure(26),or its isomer 1,4-thiazine-3-one structure(27) and the analog(28).All of these target compounds belong to novel structural heterocycle systems,their synthetic work has a certain chanllenge.This study has potent scientific significance by accumulating new knowledge and providing a synthetic method of such heterocycle system.
According to the retro-synthetic analysis,we successfully synthesized the key three-ring precusors(36,39) of the target compounds,using 4-methoxyaniline as the starting material and through two routes respectively.Since the change of A-ring structure,the Sharpless AD reaction of 9,10-double bond in 36 and 39 did not occour successfully,therefor the preparation of corresponding 9,10-dicamphanoyl analogs did not complete.However,the single 10-hydroxyl intermediate was obtained via epoxidation followed by bromo-hydroxylation,and further camphanic esteration to get 10-camphanoyl ester analog(144),which is on biological testing.
Structural modification of A ring of DCK such as replacingα-pyranone ring by ),-style(DCP 69,70) was recently reported to have potent inhibitory activity(EC_(50)= 0.00032μM,TI=116200).This result demonstrated the modification of A ring has potential foreground and merits further exploration.
Combind the research results of DCP with the SAR knowledge of DCK accumulated throgh the former structural modification,in order to exploring the effection of intact A ring and C ring to the activiy,a series of new Seco-DCK analogs were designed and synthesized.The simplest effective skeleton moiety and necessary pharmacophores were in searching of by cleavaging different carbon bond of A ring or C ring.Four series of seco-DCK analogs were successfully synthesized.
Seco-DCK analog is a new breakthrough in the research on anti-HIV drug DCKs which is a novel HIV inhibitor and has not been reported.Thereinto,compound 74 exhibits excellent anti-HIV activity(IC_(50)＞25μg/mL(58.4μM),EC_(50)＜0.025μg/mL (0.058μtM),TI＞1000),compound 71b has a potent extent of activity(IC_(50)＞25μg/mL(39.04μM),EC_(50)＜0.12μg/mL(0.19μM),TI＞208),compound 73 and 75 still has a little acitivy(IC_(50)＞25μg/mL(39.2μM),EC_(50)=16.2μg/mL(25.4μM), TI=1.7;IC_(50)=＞25μg/mL(56.5μM),EC_(50)=15.8μg/mL(35.7μM),TI=1.83), and compound 72 loses activity completedly.The accurate bioactive data of some other target prodcuts are still in testing.By comparison,some new information of the anti-HIV SAR of the seco-DCK analogs and the aspect of biological target molecule binding with them could be obtained as followed:
(1) The C_2-C_3 seco-A ring DCK analog of 4-Me-DCK(71b) still maintained potent anti-HIV activity which indicated the integrality of A ring merited further study and the seco-A ring DCK analog was possessed of more modified room.Whether the interaction of A ring to receptor is related with hydrogen bond、electronic effection or room combination will be illustrated by further investigating the seco-A ring analog. Accordingly,it will provide new hints for design,synthesis and search of new structural type of anti-HIV drugs.
(2) The compound 72 lost activity may be due to the pharmacophores of two bulky (S)-(-)-camphanoyl groups away from the original 9,10-binding district of DCK, which demonstrated the camphanoyl groups pharmacophores should be maintained at 8-position of coumarin ring.
(3) Compound 73 and 75 have a little acitivy,that explored in the area of binding with receptor there only exist a narrow cavity on theα-side at 9,10-positoin of molecule.In binding site 10-camphanoyl group was must located theβ-side of molecule plane.The activity would decline dramatically while 10-α-H was changed to CH_3 or bigger group.This is consistent with the strict requirment for the 3'R,4'R-configurations of DCKs.
(4) Compound 74 exhibited excellent activity demonstrated that the camphanoyl group at the 10-position in DCK was much more essential than 9-camphanoyl,and the integrity of C ring was also not necessary absolutely.The C ring seco-DCK has small molecular weight,and its character of logP value,solubility and biological availability might be better than 4-Me-DCK.At the same time,the metabolic caused by the two bulky camphanoyl groups in 4-Me-DCK could be avoided.Additionaly,the simplified structure,especially the lack of the chiral requirement was easy to be synthesized.All of these will be of advantage to develop a drug.These preliminary results provide us some useful hints and foundation for further research of new type HIV inhibitory agents.
We designed and synthesized a series of analogs(110-117) using compound 74 as hit.And the detailed information will be offered when the results are returned.
Additionally,compound 71b exhibited some extent of inhibitory activity of HCV, which proived us a new leading compound to enrich and develop our anti-viral research content.
Some accidental reactions were discovered and studied in detail during synthesis. The structure of the accidental products were determined and the mechanism was discussed and explained,which offered some new knowledge for the synthetic methods and chemical properties of these compounds.
Design,Synthesis of Benzothiazoline Analogs and HIV Inhibitory Activity:
1.The synthesized N-methyl-2-arylbenzothiazolines(2),o-(N-aryloyl-N-methyl-amino) phenyl disulfides(3) and 2-arylthiazolium halide(4) were screened for VEGF inhibitory activity in the human breast cancer cell MDA-MB-231 in comparison with 2-ME.Three classes of novel compounds 2,3 and 4 exhibited potent inhibitory activities against VEGF with millimolar or sub-millimolar values of EC_(50).Among them,some compounds showed potent VEGF inhibitory activities and selectivities as 2b(EC_(50)=0.07mM,SI=25);21(EC_(50)=0.115mM,SI＞32);3g(EC_(50)=0.03mM, SI＞32);4b(EC_(50)＜0.15mM,SI＞32),respectively,which were about 10 fold of those of 2-ME(EC_(50)=0.49mM,SI=3.37).The scaffolds of 2 were privileged and merited further investigation as VEGF inhibitors.
2.The solid N-methyl-2-monoarylbenzothiazolines(2) are stable and can be stored in atmosphere,whereas they present different behaviors in different solvents.They are relatively stable in alcohol and DMSO-H_2O.However,in other organic solvents such as acetone,CH_2Cl_2,CHC13 and EtOAc etc.,an oxidation-coupling reaction occurred spontaneously to give the corresponding disulfide dimmers(3).The substituents at 2-phenyl rings,reaction temperature and the acidities of the solutions exerted obvious impacts on the reaction rates and yields of 3.
3.Duing expanding the applicability of pTS/vinyl ether as deprotecion reagents against thiazolins found by ourselves,we found that the benzothiazolines from arylaldehydes were easy to be destroyed,some 2-mono substituented benzothiazolines could be converted to benzothiazolium pTS salts.The deprotection method of THF/HCl system was suitable to 2,2-dialkyl substituted benzothiazolines;as to 2-mono substituented benzothiazolines,the method can not occur deprotection and held back their radical reaction to occur.Moreover,CH_3I/THF/H_2O system was also suitable for the deprotection of benzothizaolines.These different deprotection reagents and their selectivity in deprotection reaction gave us a clue to organic synthesis.
Total of 180 compounds were synthesized in this research among them,90 compounds were new compounds.The structure of all new compounds were determined by spectra.
(一) DCK类似物的设计、合成和HIV抑制活性研究
Suksdorfin(1)是美国北卡大学药学院K.H.Lee课题组从植物LomatiumSuksdorfii的果实中分离而得的双氧杂三环稠杂环化合物,具有明显抗HIV活性(EC_(50)=2.6±2.1μM,TI=30.6±22.4,TI=therapeutic index IC_(50)/EC_(50))。Lee小组以此化合物为先导,进行了一系列的结构修饰和生物活性观察,先后获得DCK(2)(EC_(50)4×10~_(-4)μM,TI=136719)和4-甲基-DCK(11)(EC_(50)=1.57×10~(-7)μM,TI＞10~9)等化合物,其极低的EC_(50)值和极高的TI值引起了极为广泛的关注。
最近的药理作用机理研究表明,HIV-1逆转录酶可能是DCK类化合物的作用靶点,DCK类化合物不明显抑制依赖RNA的DNA合成,而对依赖DNA的DNA聚合酶的活性具有强的抑制作用,其体外测定的高活性和选择性以及独特药理作用位点,使得DCK类化合物成为非常有潜力的新结构类型抗HIV药物研究领域。因此,对DCK类化合物进一步的化学修饰和结构改造研究,进而揭示其结构与活性之间的关系,一方面可以为寻求活性更好的先导化合物提供信息和线索,同时可以探测与之相结合的作用靶点生物大分子的模型和结构信息,对研究这类化合物的分子药理作用机制具有重要的学术意义。
近年来,本课题组相继完成了用N,N-,O,N-,N,O-,O,S-,S,O-及O,C-分别代替DCK类化合物中A环或C环原有的氧原子而形成的三环稠杂环衍生物的合成及生物活性测试,其中1-thio-DCK(22a)、7-thio-DCK(21a)和4-甲基-DCK的内酰胺类似物(17a)(N,O-杂)均显示出优异的抗HIV活性;7-carbon-DCK(24b,25)的活性有一定程度下降,说明在DCK的7-位可能与靶点间存在电效应。
在这些结果的基础上,我们进一步开展了针对DCK类化合物A环结构骨架的化学修饰工作。设计了保留化合物(23a)中的1-位S原子,将4-位C原子替换成N原子的1,4-噻嗪-2-酮结构(26)及其异构体1,4-噻嗪-3-酮结构(27)和相应的类似物(28),进行合成和生物活性探索。这些目标化合物均属结构新颖的杂环体系,在化学合成上存在着一定的难度和挑战性,因此本工作对该类杂环化合物合成方法的探索和发展具有一定的学术意义。
根据逆合成分析法,以对甲氧基苯胺为起始原料,分别经过两条合成路线,成功合成了目标化合物的关键三环结构前体化合物(36,39)。在构键9,10-位羟基的时候,发现上述三类A环结构的改变,使9,10-位双键不能顺利发生Sharpless双羟化反应,因而未能完成含9,10-双樟脑酸酯的目标化合物。但通过环氧化、及溴羟化反应的探索,得到了10-位单羟基的前体,并进一步樟脑酰化合成了10-单樟脑酸酯DCK类似物(144)送活性测试。
2004年Lee课题组报道了对A环进行结构改造的DCK类化合物的新进展,即将α-吡喃酮环替代为γ-吡喃酮环(DCP 69,70),结果表明化合物70也具有相当的活性(EC_(50)=0.00032μM,TI=116200)。这一结果证明了对DCK的香豆素型A环的结构改造,是有探索前景和值得进一步研究的。
结合DCP类化合物的研究成果和前期研究对DCK类化合物结构修饰过程中积累的对构效关系认识和信息,为了探索A环和C环完整性对活性的影响,进行了Seco-DCK类新结构类似物的设计和合成研究。通过断裂A环和C环的不同碳链位置来剖析结构,寻找最简洁的有效骨架单元和必要药效团,为进一步阐明构效关系提供有用的信息。成功地合成了以下四个系列的Seco-DCK类似物:
Seco-DCK类似物是DCK系列抗HIV药物研究中一个结构上的新突破,部分目标化合物的初步活性结果显示具有显著的抗HIV活性,是一类未见文献报道的新结构类型的HIV抑制剂。其中,化合物74表现出良好的抗HIV活性(IC_(50)＞25μg/mL(58.4μM),EC_(50)＜0.025μg/mL(0.058 gM),TI＞1000),化合物71b表现出一定的抗HIV活性(IC_(50)＞25μg/mL(39.04μM),EC_(50)＜0.12μg/mL(0.19μM),TI＞208),化合物73和75则表现出稍弱的抗HIV活性(IC_(50)＞25μg/mL(39.2μM),EC_(50)=16.2μg/mL(25.4μM),TI=1.7;IC_(50)=＞25μg/mL(56.5μM),EC_(50)=15.8μg/mL(35.7μM),TI=1.83),化合物72则完全失去了活性。部分目标化合物的最终精确活性数据尚在测定中。通过比较,可以得出以下一些DCK类衍生物抗HIV构效关系及与其相作用的生物靶分子结构的新信息和新认识:
(1) 4-Me-DCK的A环C_2-C_3位开环后的类似物71b仍保持了一定的的抗HIV活性,说明对A环完整性是否有必要值得深入研究,揭示了A环开环类似物的研究,具有进一步修饰的空间。A环部分与受体的结合是通过氢键、电效应还是空间上的嵌合可通过对A环开环类似物的深入研究得以进一步阐明,从而为设计合成和寻找新结构类型的抗HIV药物提供新的线索。
(2)化合物72活性的消失说明可能由于两个樟脑酰基药效团的优势构象在空间上远离了原来DCK类的9,10-位靶点结合区域,以致活性的消失。从而证明了樟脑酰基药效团应该保留在香豆素环8-位取代基上。
(3)化合物73和75仅保留了较弱的活性,揭示了受体在与DCK类化合物9,10-位樟脑酸酯结合的位点,在α-面仅存在一个非常狭小的空穴。10-位樟脑酸酯处于分子β-面与受体靶点相结合,其10-位α-面的H改变为-CH3后活性显著下降,α-面更大的基团将导致活性的大幅度下降.此点与DCK类化合物中两个樟脑酸酯基严格的构型要求的经验相一致。
(4)化合物74保留了较强的活性,说明DCK中10-位的樟脑酰基是必要基团,而9-位的樟脑酰基对药效的影响并非十分重要;C环的完整性也不是绝对必要的;而且这类C环Seco-DCK化合物的分子量大大减小、药物设计软件显示log P值、溶解度和生物利用度都有可能好于4-Me-DCK,同时也避免了4-Me-DCK类化合物中由于两个空间拥挤邻位顺式樟脑酯大基团的存在而造成代谢不稳定的影响。此外,由于结构的简化,特别是去除了分子中的手性要求,在合成上大大简化了难度,有利于成药性的提高。这些初步研究结果,为新一类HIV抑制剂的深入研究提供了线索,打下了重要基础。
我们还以化合物74为hit设计合成了一系列类似物(110-117),待活性结果返回后可以提供更详细的信息。
另外,化合物71b在HCV的活性筛选中表现出了一定的活性,为今后的研究提供了一个新的先导化合物,我们可以以其为hit进行设计研究,丰富和扩展我们的抗病毒药物研究内容。
在合成中遇到的一些化学反应意外行为进行了较细致的研究,分别鉴定了产物的结构并解释了异常产物形成的原因,对该类化合物的合成方法和化学性质提供了新知。
(二)苯并噻唑啉衍生物的设计、合成和VEGF抑制活性研究
1.以邻甲氨基苯硫酚和各种醛、酮化合物缩合合成的2-取代苯并噻唑啉化合物
(2)及其衍生物(3,4)在VEGF的活性筛选中均表现出一定程度的抑制作用;其中个别化合物表现出了较好的活性水平(2b(EC_(50)=0.07 mM,SI=25);21(EC_(50)=0.115 mM,SI＞32);3g(EC_(50)=0.03 mM,SI＞32);4b(EC_(50)＜0.15mM,SI＞32));该类化合物的VEGF抑制作用未见文献报道,为新结构VEGF抑制剂的寻找和发现提供了新的信息。
2.发现了2-位单取代苯并噻唑啉化合物普遍存在的自发游离基氧化偶联反应现象,并对影响该反应的因素进行了细微深入的研究:在大多数有机溶剂中均会自发发生氧化偶联反应生成相应的二硫化合物;在醇类溶剂或有少量酸存在的的情况下则会抑制该类反应的发生;这类化合物发生的速率与2-位苯环上的取代基有关:温度可以显著提高该类化合物反应速率和转化率。对反应过程中得到的多种意外产物确证了结构,丰富了该类杂环化合物化学的新认识。
3.对采用苯并噻唑啉作为羰基保护基和脱保护的方法进行了拓展研究。在对课题组发现的pTS/vinyl ether脱保护法扩展底物的研究中发现:对于由芳醛形成的噻唑啉底物该方法过于剧烈,会将底物破坏,产生复杂的聚合物;而和某些2-单芳基取代噻唑啉化合物反应时会定量生成季胺盐。由酮形成的噻唑啉,即2-位双取代的噻唑啉底物可用浓盐酸脱保护,对于2-位单取代的噻唑啉底物则盐酸的存在可以抑制其氧化偶联游离基反应的发生,过量的浓盐酸会生成相应的噻唑季胺盐.此外,还发现了CH_3UTHF/H_2O体系也可进行该类化合物的脱保护。不同脱保护试剂的研究以及在脱保护反应中选择性行为,为在有机合成上的应用提供了新的线索。
上述两部分研究共合成化合物180个,其中90余个是未见文献报道的新化合物,均经波谱测定确证结构。
This dissertation has two parts of research as followed:
Design,Synthesis of DCK Analogs and HIV Inhibitory Activity:
Suksdorfin(1),a natural product isolated from the fruit of Lomatium Suksdorfii, has an angular pyranocoumarin skeleton with interesting biological properties, especially its anti-HIV activity(EC_(50)=2.6±2.1μM,TI=30.6±22.4,TI= therapeutic index IC_(50)/EC_(50)).Structural modification of 1 yielded DCK(2) and 4-methyl-DCK(11),which demonstrated extremely potent inhibitory activity against HIV-1 replication in H9 lymphocytic cells(EC_(50)=4×10~(-4)μM,TI=136719 and EC_(50) =1.57×10~(-7)μM,TI＞10~9,respectively).
The recent mechanistic studies indicated that HIV-1 RT is possibly the target of DCK and DCK is a unique HIV-1 RT inhibitor that inhibits the DNA-dependent DNA polymerase activity.In contrast,DCK did not significantly affect the RNA-dependent DNA polymerase activity.Due to its unique mode of action,DCK and its derivatives with high activity and selectivity become an attactive new anti-HIV drug research field.Accordingly,selected modifications on DCK skeleton are highly desirable in order to identify the pharmacophores in this class of potent anti-HIV agents and explore the structural aspect of the target bio-molecule(s).To this end,a variety of novel DCK analogs containing N,N-,O,N-,N,O-,O,S-,S,O- or O,C- by displacing the O,O atoms in the DCK skeleton were synthesized previously in our group.The structural modifications of 4-methyl-DCK by replacing the ring oxygen atom of DCK with a sulfur or a nitrogen atom(22a,23a and 17a) demonstrated that these analogs also exhibited potent inhibitory effects on HIV-1 replication in H9 lymphocytes;some O,C- analogs(24b,25) which showed lower inhibitory effects implied that there probably was a electronic effect at 7-position with the target.
On the basis of these results,we have expanded further structural modification aiming at the A ring of DCK.Keeping the S atom at the 1-position of compound(23a) and replacing the C to N atom at the 4-position,we designed,synthesized and bioactively explored 1,4-thiazine-2-one structure(26),or its isomer 1,4-thiazine-3-one structure(27) and the analog(28).All of these target compounds belong to novel structural heterocycle systems,their synthetic work has a certain chanllenge.This study has potent scientific significance by accumulating new knowledge and providing a synthetic method of such heterocycle system.
According to the retro-synthetic analysis,we successfully synthesized the key three-ring precusors(36,39) of the target compounds,using 4-methoxyaniline as the starting material and through two routes respectively.Since the change of A-ring structure,the Sharpless AD reaction of 9,10-double bond in 36 and 39 did not occour successfully,therefor the preparation of corresponding 9,10-dicamphanoyl analogs did not complete.However,the single 10-hydroxyl intermediate was obtained via epoxidation followed by bromo-hydroxylation,and further camphanic esteration to get 10-camphanoyl ester analog(144),which is on biological testing.
Structural modification of A ring of DCK such as replacingα-pyranone ring by ),-style(DCP 69,70) was recently reported to have potent inhibitory activity(EC_(50)= 0.00032μM,TI=116200).This result demonstrated the modification of A ring has potential foreground and merits further exploration.
Combind the research results of DCP with the SAR knowledge of DCK accumulated throgh the former structural modification,in order to exploring the effection of intact A ring and C ring to the activiy,a series of new Seco-DCK analogs were designed and synthesized.The simplest effective skeleton moiety and necessary pharmacophores were in searching of by cleavaging different carbon bond of A ring or C ring.Four series of seco-DCK analogs were successfully synthesized.
Seco-DCK analog is a new breakthrough in the research on anti-HIV drug DCKs which is a novel HIV inhibitor and has not been reported.Thereinto,compound 74 exhibits excellent anti-HIV activity(IC_(50)＞25μg/mL(58.4μM),EC_(50)＜0.025μg/mL (0.058μtM),TI＞1000),compound 71b has a potent extent of activity(IC_(50)＞25μg/mL(39.04μM),EC_(50)＜0.12μg/mL(0.19μM),TI＞208),compound 73 and 75 still has a little acitivy(IC_(50)＞25μg/mL(39.2μM),EC_(50)=16.2μg/mL(25.4μM), TI=1.7;IC_(50)=＞25μg/mL(56.5μM),EC_(50)=15.8μg/mL(35.7μM),TI=1.83), and compound 72 loses activity completedly.The accurate bioactive data of some other target prodcuts are still in testing.By comparison,some new information of the anti-HIV SAR of the seco-DCK analogs and the aspect of biological target molecule binding with them could be obtained as followed:
(1) The C_2-C_3 seco-A ring DCK analog of 4-Me-DCK(71b) still maintained potent anti-HIV activity which indicated the integrality of A ring merited further study and the seco-A ring DCK analog was possessed of more modified room.Whether the interaction of A ring to receptor is related with hydrogen bond、electronic effection or room combination will be illustrated by further investigating the seco-A ring analog. Accordingly,it will provide new hints for design,synthesis and search of new structural type of anti-HIV drugs.
(2) The compound 72 lost activity may be due to the pharmacophores of two bulky (S)-(-)-camphanoyl groups away from the original 9,10-binding district of DCK, which demonstrated the camphanoyl groups pharmacophores should be maintained at 8-position of coumarin ring.
(3) Compound 73 and 75 have a little acitivy,that explored in the area of binding with receptor there only exist a narrow cavity on theα-side at 9,10-positoin of molecule.In binding site 10-camphanoyl group was must located theβ-side of molecule plane.The activity would decline dramatically while 10-α-H was changed to CH_3 or bigger group.This is consistent with the strict requirment for the 3'R,4'R-configurations of DCKs.
(4) Compound 74 exhibited excellent activity demonstrated that the camphanoyl group at the 10-position in DCK was much more essential than 9-camphanoyl,and the integrity of C ring was also not necessary absolutely.The C ring seco-DCK has small molecular weight,and its character of logP value,solubility and biological availability might be better than 4-Me-DCK.At the same time,the metabolic caused by the two bulky camphanoyl groups in 4-Me-DCK could be avoided.Additionaly,the simplified structure,especially the lack of the chiral requirement was easy to be synthesized.All of these will be of advantage to develop a drug.These preliminary results provide us some useful hints and foundation for further research of new type HIV inhibitory agents.
We designed and synthesized a series of analogs(110-117) using compound 74 as hit.And the detailed information will be offered when the results are returned.
Additionally,compound 71b exhibited some extent of inhibitory activity of HCV, which proived us a new leading compound to enrich and develop our anti-viral research content.
Some accidental reactions were discovered and studied in detail during synthesis. The structure of the accidental products were determined and the mechanism was discussed and explained,which offered some new knowledge for the synthetic methods and chemical properties of these compounds.
Design,Synthesis of Benzothiazoline Analogs and HIV Inhibitory Activity:
1.The synthesized N-methyl-2-arylbenzothiazolines(2),o-(N-aryloyl-N-methyl-amino) phenyl disulfides(3) and 2-arylthiazolium halide(4) were screened for VEGF inhibitory activity in the human breast cancer cell MDA-MB-231 in comparison with 2-ME.Three classes of novel compounds 2,3 and 4 exhibited potent inhibitory activities against VEGF with millimolar or sub-millimolar values of EC_(50).Among them,some compounds showed potent VEGF inhibitory activities and selectivities as 2b(EC_(50)=0.07mM,SI=25);21(EC_(50)=0.115mM,SI＞32);3g(EC_(50)=0.03mM, SI＞32);4b(EC_(50)＜0.15mM,SI＞32),respectively,which were about 10 fold of those of 2-ME(EC_(50)=0.49mM,SI=3.37).The scaffolds of 2 were privileged and merited further investigation as VEGF inhibitors.
2.The solid N-methyl-2-monoarylbenzothiazolines(2) are stable and can be stored in atmosphere,whereas they present different behaviors in different solvents.They are relatively stable in alcohol and DMSO-H_2O.However,in other organic solvents such as acetone,CH_2Cl_2,CHC13 and EtOAc etc.,an oxidation-coupling reaction occurred spontaneously to give the corresponding disulfide dimmers(3).The substituents at 2-phenyl rings,reaction temperature and the acidities of the solutions exerted obvious impacts on the reaction rates and yields of 3.
3.Duing expanding the applicability of pTS/vinyl ether as deprotecion reagents against thiazolins found by ourselves,we found that the benzothiazolines from arylaldehydes were easy to be destroyed,some 2-mono substituented benzothiazolines could be converted to benzothiazolium pTS salts.The deprotection method of THF/HCl system was suitable to 2,2-dialkyl substituted benzothiazolines;as to 2-mono substituented benzothiazolines,the method can not occur deprotection and held back their radical reaction to occur.Moreover,CH_3I/THF/H_2O system was also suitable for the deprotection of benzothizaolines.These different deprotection reagents and their selectivity in deprotection reaction gave us a clue to organic synthesis.
Total of 180 compounds were synthesized in this research among them,90 compounds were new compounds.The structure of all new compounds were determined by spectra.
引文
[1]Huang,L.;Kashiwada,Y.;Cosentino,L.M.;Fan,S.;Lee,K.H.Anti-AIDS agents.14.3',4'-di-O-(-)-Camphanoyl-(+)-cis-Khellactone and related compounds---a new class of potent anti-HIV agents[J].Bioorg.Med.Chem.Lett.1994,4(4):593-598.
[2]Xie,L,;Takeuchi,Y,;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents.37.Synthesis and structure-activity relationships of(3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents[J].J.Med.Chem.1999,42(14):2662-2672.
[3]Huang,L.;Kashiwada,Y.;Cosentino,L.M.;Fan,S.;Chen,C.H.;McPhail,A.T.;Fujioka,T.;Mihashi,K.;Lee,K.H.Anti-AIDS agents.15.Synthesis and anti-HIV activity of dihydroseselins and related analogs[J].J.Med.Chem.1994,37(23):3947-3955.
[4]Takeuchi,Y.;Xie,L.;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents.28.Synthesis and anti-HIV activity of methoxy substituted 3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellactone(DCK) analogues[J].Bioorg.Med.Chem.Lett.1997,7(20):2573-2578.
[5]Xie,L.;Takeuchi,Y.;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents.33.Synthesis and anti-HIV activity of mono-methyl substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone(DCK) analogues[J].Bioorg.Med.Chem.Lett.1998,8(16):2151-2156.
[6]Xie,L.;Takeuchi,Y.;Concentino,L.M.;McPhail,A.T.;Lee,K.H.Anti-AIDS agents.42.Synthesis and anti-HIV activity of disubstituted (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone analogues[J].J.Med.Chem.2001,44(5):664-671.
[7]Yang,Z.Y.;Xia,Y.;Xia,P.;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents.31.Synthesis and anti-HIV activity of 4-substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone(DCK) thiolactone analogs[J].Bioorg.Med.Chem.Lett.1998,8(12):1483-1486.
[8]Yang,Z.Y.;Xia,Y.;Xia,P.;Cosentino,L.M.;Lee,K.H.Antitumor agents 187:Synthesis and cytotoxicity of substituted 8,8-dimethyl-2H,8H-pyrano[6,5-h]quinoline-2-one and related compounds[J]. Bioorg.Med.Chem.Lett.1999,9(5):713-716.
[9]Yang,Z.Y.;Xia,Y.;Xia,P.;Brossi,A.;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents part 41:Synthesis and anti-HIV activity of 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone(DCK) lactam analogues[J].Bioorg.Med.Chem.Lett.2000,10(10):1003-1005.
[10]Xie,L,;Yu,D.;Wild,C.;Allaway,G.;Turpin,J.;Smith,P.C.;Lee,K.H.Anti-AIDS agents.52.Synthesis and anti-HIV activity of hydroxymethyl (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives[J].J.Med.Chem.2004,47(3):756-760.
[11]Huang,L.;Yuan,X.;Yu,D.L.;Lee,K.H.;Chen,C.H.Mechanism of action and resistant profile of anti-HIV-1 coumarin derivatives[J].Virology 2005,332(2):623-628.
[12]Zhang,Q.;Chen,Y.;Zheng,Y.Q.;Xia,P.;Xia,Y.;Yang,Z.Y.;Bastow,K.F.;Morris-Natschke,S.L.;Lee,K.H.Synthesis and bioactivity of 4,10-dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9-carboxylic acid and its esters[J].Bioorg.Med.Chem.2003,11(6):1031-1034.
[13]郑云红.孕激素新药诺美孕酮乙酸酯及O,N杂三环杂环化合物的合成方法和生物活性研究[D].上海:上海医科大学,2000年5月.
[14]Chen,Y.;Zhang,Q.;Zhang,B.N.;Xia,P.;Xia,Y.;Yang,Z.Y.;Kilgore,N.;Wild,C.;Morris-Natschke,S.L.;Lee,K.H.Anti-AIDS agents.56.Synthesis and anti-HIV activity of 7-thia-di-O-(-)-camphanoyl-(+)-cis-khellactone (7-thia-DCK) analogs[J].Bioorg.Med.Chem.2004,12(24):6383-6387.
[15]Xia,P.;Yin,Z.J.;Chen,Y.;Zhang,Q.;Zhang,B.N.;Xia,Y.;Yang,Z.Y.;Kilgore,N.;Wild,C.;Morris-Natschke,S.L.;Lee,K.H.Anti-AIDS agents.Part 58.Synthesis and anti-HIV activity of 1-thia-di-O-(-)-camphanoyl-(+)-cis-khellactone(1-thia-DCK) analogues[J].Bioorg.Med.Chem.Lett.2004,14(12):3341-3343.
[16]Zhang,Q.;Chen,Y.;Xia,P.;Xia,Y.;Yang,Z.Y.;Yu,D.L.;Morris-Natschke,S.L.;Lee,K.H.Anti-AIDS agents.Part 62.Anti-HIV activity of 2'-substituted 4-methyl-3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone(4-methyl DCK)analogs[J].Bioorg.Med.Chem.Lett.2004,14(23):5855-5857.
[17]Yang,W;Shao,X.H.;Xia,P.;Xia,Y.;Yang,Z.Y.;Yu,D.L.;Morris-Natschke,S.L.;Lee,K.H.Anti-AIDS agents.Part 72.Bioisosteres(7-carbon-DCKs) of the potent Anti-HIV lead DCK[J].Bioorg.Med.Chem.Lett.2007,17(23):4316-4319.
[18]郑云红,夏奕,杨征宇,张倩,陈瑛,夏鹏.8,9-二氢-2H-吡喃并[5,6-g]喹啉-2-酮衍生物的合成[J].有机化学,2001,21(3):231-234.
[19]陈瑛,夏奕,杨征宇,张倩,夏鹏.4-甲基-7-巯基-2(1H)-喹啉酮的合成[J].有机化学,2001,21(5):369-371.
[20]王洋,夏鹏.4-氯-1,7-二羟基二氢化茚的合成及意外醚化反应的研究[J].有机化学,2003,23(12):1362-1365.
[21]王洋,卢美艳,夏鹏.4-甲基-7,10-二氢苯并[h]香豆素的合成研究[J].有机化学,2003,23(12):1396-1399.
[22]Zhang,Q.;Chen,Y.;Xia,Y.;Yang,Z.Y.;Xia,P.New heterocycles:4-Methyl-2H-pyrano[6,5-f]cycloalka-[2,1-b]2H-chromen-2-ones[J].Heterocycles 2004,63(7):1637-1643.
[23]Henning SV;Scheutzow P;Schlaf H;Quast H.Liebigs Ann.Chem.1972,765:110-25.
[24]Stuckwisch,C.G.Municipal Univ.of Wichita,KS,Derivatives of 2-amino-6methoxybenzothiazole [J].Journal of the American Chemical Society,1949,71:3417.
[25]Dannley,Ralph L.;Zazaris,Dimitri A.Synthesis of 2-aminobenzenethiol hydrochlorides[J].Canadian Journal of Chemistry,1965,43(9):2610-12.
[26]Sastry,C.V.Reddy;Rao,K.Srinivasa;Krishnan,V.S.H.;Lovekar,C.D.;Kondaiah,S.;Sai,G.S.T.Synthesis and anthelmintic activity of methyl [5(6)-[(3-oxo-1,4-benzothiazin-7-yl]oxy)-benzimidazole]-2-carbamates[J].Indian Journal of Chemistry,Section B:Organic Chemistry Including Medicinal Chemistry.1990,29B(3):297-9.
[27]Sastry,C.V.Reddy;Rao,K.Srinivasa;Sai,G.S.T.Synthesis and anthelmintic activity of methyl[5(6)-[(3-oxo-1,4-benzothiazin-7-yl]oxy)benzimidazole ]-2-carbamates[J].Indian Journal of Chemistry,Section B:Organic Chemistry Including Medicinal Chemistry.1990,29B(3):297-9.
[28]David,B.;Mark,R.D.;Graham,R.G.;Inderjit,S.M..Copper(Ⅰ) iodide:A Catalyst for the Improved Synthesis of Aryl Propargyl Ethers[J].Synthesis,EN.1995,6:707-712.
[29]Toya,Yoshiaki;Takagi,Masaharu;Nakata,Hisao;Goto,Toshio.A convenient synthetic method of 2-cyano-6-methoxybenzothiazole.[J].Bulletin of the Chemical Society of Japan.1992,65(2):392-5.
[30]Delhomel,J.F.;Yous,S.;Depreux,P.;Lesieur,D.Synthesis of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives as potential beta-3-adrenergic receptor ligands[J].Journal of Heterocyclic Chemistry.2001,38(3),633-639.
[31]Gordon,B.;Frederick,C.;John,M.E.;Diane,L..Variation in the Aromatic Ring of Cromakalim:Antihypertensive Activity of Pyranoridines and 6-Alkyl-2H-1-benzopyrans[J].J.Med.Chem.1990,33:3023-3027.
[32]Yu,D.L.;Brossi,A.;Kilgore,N.;Wild,C.;Allaway,G.;Lee,K.H.Anti-HIV agents.Part 55:3'R,4'R-di-(O)-(-)-camphanoyl-2',2'- dimethyldihydropyrano [2,3-f]chromone(DCP),a novel anti-HIV agent[J].Bioorg.Med.Chem.Lett.2003,13(9):1575-1576.
[33]Yu,D.L.;Chin-Ho,C.;Brossi,A.;Lee,K.H.Anti-AIDS agents.60:3'R,4'R-di-(O)-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) as potent anti-HIV agent[J].J.Med.Chem.2004,47:4072-4082.
[34]Asranjaneyulu;Mallavadhani,U.V.;Venkateswarlu,Y.;Ramaprasad,A.V.Reaction of Acetic Anhydride/Zinc Chloride Reagent with Phenols:Improved Yields of Hydroxyacetophenones[J].Indian Journal of Chemistry.1987,26B:823-826.
[35]Gulati,Khusshal C.;Seth,Sant R.;Venkataraman,Krishnasami.Synthetical experiments in the chromone group.ⅩⅢ.Hydroxy-2-styrylchromones[J].Journal of the Chemical Society.1934,1765-7.
[36]Dewick,Paul M.;Martin,Maria.Biosynthesis of pterocarpan,isoflavan and coumestan metabolites of Medicago sativa:chalcone,isoflavone and isoflavanone precursors[J]Phytochemistry.1979,18(4):597-602.
[37]Lakshmi,N.D.;Nitar,C.S.;Asoke,k.A New General Approach for Introducing Side Chain in Coumarins Utilising Bromozinc as Chemo-,Regioand Stereo-selective Reagents[J].Indian J.of Chem.1988,27B:801-805.
[38]Sharan,P.;Girl,S.;Nizamuddin.Synthesis of some 7-Hydroxy-4-methylcoumarin-8-yl Chalcones and related Iso-oxazoles as Potential Funficides[J].J.Indian Chem.1989,66:393-394.
[39]Dean,R.B.;David,K.;Janice,D.F.;Henry,R.Synthesis and Derivitization of 8-Acetylpsoralens.Acetyl Migrations during Claisen Rearrangemeng[J].J.Org.Chem.1983,48:2709-2719.
[40]Takehiko,N.A Novel Transformation of Alcohols to Thiols[J].Journal of the Chemical Society,Chemical Communications.1989,No.4:205-206.
[41]Takehiko,N.Direct Conversion of Alcohols into Thiols[J].J.Chem.Soc.Perkin Trans.,1993,1113-1117.
[1]Kesisis G.;Broxterman H.;Giaccone G..Angiogenesis inhibitors.Drug selectivity and target specificity[J].CURRENT PHARMACEUTICAL DESIGN,2007,13(27):2795-2809.
[2]Emoto M.;Tachibana K.;Iwasaki H.et al.Antitumor effect of TNP-470,an angiogenesis inhibitor,combined with ultrasound irradiation for human uterine sarcoma xenografts evaluated using contrast color Doppler ultrasound[J].CANCER SCIENCE,2007,98(6):929-935.
[3]Thotathil Z.;Jameson M.B.Early experience with novel immunomodulators for cancer treatment[J].EXPERT OPINION ON INVESTIGATIONAL DR UGS,2007,16(9):1391-1403.
[4]Sridhar SS,Shepherd FA,Targeting angiogenesis:a review of angiogenesis inhibitors in the treatment of lung cancer[J].LUNG CANCER,2003,42:S81-S91.
[5]Yokoyama Y.;Ramakrishnan S.;Binding of endostatin to human ovarian cancer cells inhibits cell attachment[J].INTERNATIONAL JOURNAL OF CANCER 2007,121(11):2402-2409.
[6]Ferrara N.VEGF and the quest for tumour angiogenesis factors[J].Nature Reviews,2002,2:7 95-803.
[7]Goodsell D.S.The Molecular Perspective:VEGF and Angiogenesis[J].Oncotogist,2002,7:569-570
[8]刘新云 朱景中 涂自良 陈燕 VEGF受体酪氨酸激酶抑制剂的研究进展.中国药师:2005,8(5):369-371
[9]Laurent F.H.;Andrew P.T.;Craig J.;et al.Design and Structure-Activity Relationship of a New Class of Potent VEGF Receptor Tyrosine Kinase Inhibitors[J].J.Med.Chem.1999,42:5369-5389
[10]Peifer C.;Stoiber,T.;Unger,et al.Design,Synthesis,and Biological Evaluation of 3,4-Diarylmaleimides as Angiogenesis Inhibitors[J].J.Med.Chem.2006;49(4):1271-1281.
[11]Potashman M.H.;Bready J.;Coxon A.et al.Design,synthesis,and evaluation of orally active Benzimidazoles and Benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors[J].J.Med.Chem.50(18): 4351-4373.
[12]Alexander S.K.;Evgueni P.et al.1H-1,2,4-Triazol-3-yl-anilines:Novel Potent Inhibitors of Vascular Endothelial Growth Factor Receptors 1 and 2[J].Chem.Biol.Drug Des.2007,69:331-337.
[13]翟鑫,王玉亚,宫平。以血管内皮生长因子及其受体为靶点的肿瘤血管生成抑制剂的研究进展。中国药物化学杂志,2006,16(1):60-63
[14]Kirkpatrick K.;Ogunkolade W.;Elkak A.et al.The mRNA expression of cyclooxygenase-2(COX-2) and vascular endothelial growth factor(VEGF) in human breast cancer[J].Curt.Med.Res.Opin.2002,18(4):237-241.
[15]Pruthi R.S.;Derksen J.E.;Moore D.A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy[J].BJU Int.2004,93:275-278.
[16]Chauhan,D.;Catley,L.;Hideshima,T..Blood.2002,100(6),2187.
[17]Mabjeesh,N.J.;Escuin D.;LaVallee T.M..Cancer Cell.2003,3,363.
[18]Stafford,S.J.et.al;J.Sung.Res..2005,125,104.
[19]Bradshaw,T.D.;Wrigley,S.;Shi,D.F.British Journal of Cancer,1998,77(5),745.
[20]Geoffrey,W.;Tracey,B.;Patrizia,D.Bioo.Med Chem.Lett.2000,10,513.
[21]James,M.H.;Hollis Showalter,H.D..Pharmacol.Then.1999,82,169.
[22]Bei Na Zhang,king Chen,Qian Zhang,Peng Xia.Some Unreported By-Products From The Reaction Of 1,4-Dien-3-One Steroids With 2-(Methylamino)Benzethiol/BF_3[J].Steroids,70(2),111-116(2005).
[23]Bei Na Zhang,Ying Chen,Qian Zhang,Peng Xia.A concise effective deprotection of spiro 3-cyclic thiaza ketal of steroidal 1,4-dien-3-one[J].Steroids,72(1),60-63(2007).
[24]Hidenori,C.;Shun-ichiro,K.;Nishiki I.Bull.Chem.Soc.Jpn.1989,62,1215.
[25]Mikio,H.;Tadashi,K.;Hiroshi,S.Yakugaku Zasshi,1975,95(6),634.
[26]Citterio,A.;Gentile,A.;Minisci,F.Tetrahedron Letter,1982,23,5587.
[27]Minisci,F.;Vismara,E.;Fonatana,F.J.Org.Chem.1989,54,5224.
[28]Human VEGF Quantitative Reagent Kit.http://www.innogent-cn.com.
[29]VEGF bioactivity detection:The single human breast cancer cell MDA-MB-231 suspension in 1640 Medium with 10%Foetal Bovine Serum at a concentration of 10~4-10~5 cells per milliliter was prepared.Each sample to be detected were resolved in distilled water or 0.5% DMSO and diluted to multipropor on concentration. 90μL cell suspension and 10μL sample solution was mixed and culvitated in each well of 96 well-micro plate at 37℃ with 5% CO_2 for three days. The IC_(50) was obtained by detecting the cell growth inhibitory rate directly using 10μL medium as the blank control. Then the VEFG inhibitory rate was detected using VEGF ELISA kit (SHENZHEN YINUOJIN Biotechnology Company). The EC_(50) was obtained by calculation from the diagram of inhibitory rate v.s. sample concentration.
[30] Dina Chelouche-Lev, Claudia P. Miller, Carmen Tellez. European Journal of Cancer, 2004,40, 2509.
1:De Clercq E.New developments in anti-HIV[J].Biochimica et Biophysica Acta,2002,1587(2):258-275.
2.De Clercq E.New anti-HIV angents and targets[J].Med Res Rev,2002,22(6):5312-5651
3.Moulard M,Lortat-Jacob H,Mondor I,Roca G,Wyatt R,Sodroski J,Zhao L,Olson W,Kwong PD,Sattentau QJ.Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp 120[J].J Virol,2000;74:1948-1960.
4.Luscher-Mattli M.Polyanions-A lost chance in the fight against HIV and other virus diseases[J].Antiviral Chem Chemother 2000;11:249-259.
5.Dragic,T.,Trkola,A.,Thompson,D.A.,Cormier,E.G.,Kajumo,F.A.,Maxwell,E.,Lin,S.W.,Ying,W.,Smith,S.O.,Sakmar,T.P.,Moore,J.P.,A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5[J].Proc.Natl Acad.Sci.U.S.A.2000.97,5639-5644.
6.Yakashima,K.,Miyake,H.,Kanzaki,N.,Yagawa,Y.,Wang,X.,Sugihara,Y.,Iizawa,Y.,Baba,M.,Highly potent inhibition of human immunodeficiency virus type 1replication by YAK-220,an orally bioavailable small-molecule CCR5 antagonist[J].Antimicrob.Agents Chemother 2005.49,3474-3482.
7.Baba,M.,Takashima,K.,Miyake,H.,Kanzaki,N.,Teshima,K.,Wang,X.,Shiraishi,M.,Iizawa,Y.,TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans[J].Antimicrob.Agents Chemother 2005.49,4584-4591.
8.Strizki,J.M.,Tremblay,C.,Xu,S.,Wojcik,L.,Wagner,N.,Gonsiorek,W.,Hipkin,R.W.,Chou,C.C.,Pugliese-Sivo,C.,Xiao,Y.,Tagat,J.R.,Cox,K.,Priestley,T.,Sorota, S., Huang, W., Hirsch, M., Reyes, R.G., Baroudy, B.M., Discovery and characterization of vicriviroc (SCH 417690), A CCR5 antagonist with potent activity against human immunodeficiency virus type 1 [J]. Antimicrob. Agents Chemother. 2005.49, 4911-4919.
9. Dorr, P., Westby, M., Dobbs, S., Griffin, P., Irvine, B., Macartney, M, Mori, J., Rickett, G., Smith-Burchnell, C., Napier, C., Webster, R., Armour, D., Price, D., Stammen, B., Wood, A., Perros, M., Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity [J]. Antimicrob. Agents Chemother. 2005.49,4721-4732.
10. Hatse, S., Princen, K., Bridger, G., De Clercq, E., Schols, D., Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4 [J]. FEBS Lett. 2002.527, 255-262.
11. Labrosse B, Treboute C, Alizon M. Sensitivity to a nonpeptide compound (RPR103611) blocking human immunodeficiency virus type 1 Env-mediated fusion depends on sequence and accessibility of the gp41 loop region [J]. J Virol 2000; 74: 2142-2150.
12. Temiz NA, Bahar I: Inhibitor binding alters the directions of domain motions in HIV-1 reverse transcriptase [J]. Proteins 2002, 49: 61-70.
13. Shen L, Shen J, Luo X, Cheng F, Xu Y, Chen K, Arnold E, Ding J, Jiang H: Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT [J]. Biophys J 2003,84: 3547-3563.
14. Gazzard BG, Pozniak AL, Rosenbaum W, Yeni GP, Staszewski S, Arasteh K, De Dier K, Peeters M, Woodfall B, Stebbing J, vant' Klooster GA: An open-label assessment of TMC 125 a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance [J]. AIDS 2003, 17:49-54.
15. Hammond JN, Raber S, Amantea M, Grettenberger H, Shetty B, Hawley P, Patick AK: Determination of capravirine inhibitory quotient in HIV infected, NNRTI-treatment experienced patients [J]. Abstract 649, 41st Annual Meeting of the American Society of Infectious Diseases: 2003. October 9-12; San Diego.
16. Pauwels R. New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections[J]. Current Opinion in Pharmacology 2004, 4:437-446
17. Pluymers, W., De Clercq, E., and Debyser, Z. HIV-1 inte-gration as a target for antiretroviral therapy: a review. Curr. Drug Targets-Infectious Disorders 2001, 7, 133-149.
18. Pannecouque C., Pluymers W., Maele B. V., Tetz V., Cherepanov P., De Clercq, E., Witvrouw M, Debyser Z. New Class of HIV Integrase Inhibitors that Block Viral Replication in Cell[J]. Culture Current Biology, Vol. 12, 1169-1177, July 23,2002
19. Okamoto H, Cujec TP, Okamoto M, Peterlin BM, Baba M, Okamoto T. Inhibition of the RNA-dependent transactivation and replication of human immunodeficiency virus type 1 by a fluoroquinoline derivative K-37 [J]. Virology 2000;272:402-408.
20. Abdel-Rahman, H. M.; Al-Karamany, G.S.; El-Koussi, N. A.; Youssef, A. F.; Kiso, Y. HIV protease inhibitors: peptidomimetic drugs and future perspectives [J]. Curr. Med. Chem. 2002, 9,1905-1922.
21. Randolph, J. T.; DeGoey, D. A. Peptidomimetic inhibitors of HIV protease [J]. Curr. Top. Med. Chem. 2004, 4, 1079-1095.
22. Rodriguez-Barrios, R; Gago, R HIV protease inhibition: limited recent progress and advances in understanding current pitfalls [J]. Curr. Top. Med. Chem. 2004, 4,991-1007.
23. Bursavich, M. G.; Rich, D. H. Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles [J]. J. Med. Chem. 2002, 45, 541-558.
24. Carr, A. Toxicity of antiretroviral therapy and implications for drug development [J]. Nat. Rev. Drug Discovery 2003,2, 624-634.
25. Wang, R; Ross, J. Atazanavir: a novel azapeptide inhibitor of HIV-1 protease [J]. Formulary 2003,38,691-702.
26. Raja, A.; Lebbos, J.; Kirkpatrick, P. Fresh from the pipeline: Atazanavir sulphate [J]. Nat. Rev. Drug Discovery 2003,2, 857-858.
27. Rusconi S, La Seta Catamancio S, Citterio P, Kurtagic S, Violin M, Balotta C, Moroni M, Galli M, d'Arminio-Monforte A. Susceptibility to PNU-140690 (tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors [J]. Antimicrob Agents Chemother 2000; 44: 1328-1332.
28.Ekegren J.K.,Unge T.,Safa M.Z.,Wallberg H.,Samuelsson B.,Hallberg A.,A New Class of HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimicking Scaffold[J].J.Med.Chem.2005,48,8098-8102.
29.天然来源具有抗HIV活性的多肽和蛋白类化合物。王建华等,中国天然药物。2004年11月第2卷第6期:321-327.
[2]Xie,L,;Takeuchi,Y,;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents.37.Synthesis and structure-activity relationships of(3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents[J].J.Med.Chem.1999,42(14):2662-2672.
[3]Huang,L.;Kashiwada,Y.;Cosentino,L.M.;Fan,S.;Chen,C.H.;McPhail,A.T.;Fujioka,T.;Mihashi,K.;Lee,K.H.Anti-AIDS agents.15.Synthesis and anti-HIV activity of dihydroseselins and related analogs[J].J.Med.Chem.1994,37(23):3947-3955.
[4]Takeuchi,Y.;Xie,L.;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents.28.Synthesis and anti-HIV activity of methoxy substituted 3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellactone(DCK) analogues[J].Bioorg.Med.Chem.Lett.1997,7(20):2573-2578.
[5]Xie,L.;Takeuchi,Y.;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents.33.Synthesis and anti-HIV activity of mono-methyl substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone(DCK) analogues[J].Bioorg.Med.Chem.Lett.1998,8(16):2151-2156.
[6]Xie,L.;Takeuchi,Y.;Concentino,L.M.;McPhail,A.T.;Lee,K.H.Anti-AIDS agents.42.Synthesis and anti-HIV activity of disubstituted (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone analogues[J].J.Med.Chem.2001,44(5):664-671.
[7]Yang,Z.Y.;Xia,Y.;Xia,P.;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents.31.Synthesis and anti-HIV activity of 4-substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone(DCK) thiolactone analogs[J].Bioorg.Med.Chem.Lett.1998,8(12):1483-1486.
[8]Yang,Z.Y.;Xia,Y.;Xia,P.;Cosentino,L.M.;Lee,K.H.Antitumor agents 187:Synthesis and cytotoxicity of substituted 8,8-dimethyl-2H,8H-pyrano[6,5-h]quinoline-2-one and related compounds[J]. Bioorg.Med.Chem.Lett.1999,9(5):713-716.
[9]Yang,Z.Y.;Xia,Y.;Xia,P.;Brossi,A.;Cosentino,L.M.;Lee,K.H.Anti-AIDS agents part 41:Synthesis and anti-HIV activity of 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone(DCK) lactam analogues[J].Bioorg.Med.Chem.Lett.2000,10(10):1003-1005.
[10]Xie,L,;Yu,D.;Wild,C.;Allaway,G.;Turpin,J.;Smith,P.C.;Lee,K.H.Anti-AIDS agents.52.Synthesis and anti-HIV activity of hydroxymethyl (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives[J].J.Med.Chem.2004,47(3):756-760.
[11]Huang,L.;Yuan,X.;Yu,D.L.;Lee,K.H.;Chen,C.H.Mechanism of action and resistant profile of anti-HIV-1 coumarin derivatives[J].Virology 2005,332(2):623-628.
[12]Zhang,Q.;Chen,Y.;Zheng,Y.Q.;Xia,P.;Xia,Y.;Yang,Z.Y.;Bastow,K.F.;Morris-Natschke,S.L.;Lee,K.H.Synthesis and bioactivity of 4,10-dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9-carboxylic acid and its esters[J].Bioorg.Med.Chem.2003,11(6):1031-1034.
[13]郑云红.孕激素新药诺美孕酮乙酸酯及O,N杂三环杂环化合物的合成方法和生物活性研究[D].上海:上海医科大学,2000年5月.
[14]Chen,Y.;Zhang,Q.;Zhang,B.N.;Xia,P.;Xia,Y.;Yang,Z.Y.;Kilgore,N.;Wild,C.;Morris-Natschke,S.L.;Lee,K.H.Anti-AIDS agents.56.Synthesis and anti-HIV activity of 7-thia-di-O-(-)-camphanoyl-(+)-cis-khellactone (7-thia-DCK) analogs[J].Bioorg.Med.Chem.2004,12(24):6383-6387.
[15]Xia,P.;Yin,Z.J.;Chen,Y.;Zhang,Q.;Zhang,B.N.;Xia,Y.;Yang,Z.Y.;Kilgore,N.;Wild,C.;Morris-Natschke,S.L.;Lee,K.H.Anti-AIDS agents.Part 58.Synthesis and anti-HIV activity of 1-thia-di-O-(-)-camphanoyl-(+)-cis-khellactone(1-thia-DCK) analogues[J].Bioorg.Med.Chem.Lett.2004,14(12):3341-3343.
[16]Zhang,Q.;Chen,Y.;Xia,P.;Xia,Y.;Yang,Z.Y.;Yu,D.L.;Morris-Natschke,S.L.;Lee,K.H.Anti-AIDS agents.Part 62.Anti-HIV activity of 2'-substituted 4-methyl-3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone(4-methyl DCK)analogs[J].Bioorg.Med.Chem.Lett.2004,14(23):5855-5857.
[17]Yang,W;Shao,X.H.;Xia,P.;Xia,Y.;Yang,Z.Y.;Yu,D.L.;Morris-Natschke,S.L.;Lee,K.H.Anti-AIDS agents.Part 72.Bioisosteres(7-carbon-DCKs) of the potent Anti-HIV lead DCK[J].Bioorg.Med.Chem.Lett.2007,17(23):4316-4319.
[18]郑云红,夏奕,杨征宇,张倩,陈瑛,夏鹏.8,9-二氢-2H-吡喃并[5,6-g]喹啉-2-酮衍生物的合成[J].有机化学,2001,21(3):231-234.
[19]陈瑛,夏奕,杨征宇,张倩,夏鹏.4-甲基-7-巯基-2(1H)-喹啉酮的合成[J].有机化学,2001,21(5):369-371.
[20]王洋,夏鹏.4-氯-1,7-二羟基二氢化茚的合成及意外醚化反应的研究[J].有机化学,2003,23(12):1362-1365.
[21]王洋,卢美艳,夏鹏.4-甲基-7,10-二氢苯并[h]香豆素的合成研究[J].有机化学,2003,23(12):1396-1399.
[22]Zhang,Q.;Chen,Y.;Xia,Y.;Yang,Z.Y.;Xia,P.New heterocycles:4-Methyl-2H-pyrano[6,5-f]cycloalka-[2,1-b]2H-chromen-2-ones[J].Heterocycles 2004,63(7):1637-1643.
[23]Henning SV;Scheutzow P;Schlaf H;Quast H.Liebigs Ann.Chem.1972,765:110-25.
[24]Stuckwisch,C.G.Municipal Univ.of Wichita,KS,Derivatives of 2-amino-6methoxybenzothiazole [J].Journal of the American Chemical Society,1949,71:3417.
[25]Dannley,Ralph L.;Zazaris,Dimitri A.Synthesis of 2-aminobenzenethiol hydrochlorides[J].Canadian Journal of Chemistry,1965,43(9):2610-12.
[26]Sastry,C.V.Reddy;Rao,K.Srinivasa;Krishnan,V.S.H.;Lovekar,C.D.;Kondaiah,S.;Sai,G.S.T.Synthesis and anthelmintic activity of methyl [5(6)-[(3-oxo-1,4-benzothiazin-7-yl]oxy)-benzimidazole]-2-carbamates[J].Indian Journal of Chemistry,Section B:Organic Chemistry Including Medicinal Chemistry.1990,29B(3):297-9.
[27]Sastry,C.V.Reddy;Rao,K.Srinivasa;Sai,G.S.T.Synthesis and anthelmintic activity of methyl[5(6)-[(3-oxo-1,4-benzothiazin-7-yl]oxy)benzimidazole ]-2-carbamates[J].Indian Journal of Chemistry,Section B:Organic Chemistry Including Medicinal Chemistry.1990,29B(3):297-9.
[28]David,B.;Mark,R.D.;Graham,R.G.;Inderjit,S.M..Copper(Ⅰ) iodide:A Catalyst for the Improved Synthesis of Aryl Propargyl Ethers[J].Synthesis,EN.1995,6:707-712.
[29]Toya,Yoshiaki;Takagi,Masaharu;Nakata,Hisao;Goto,Toshio.A convenient synthetic method of 2-cyano-6-methoxybenzothiazole.[J].Bulletin of the Chemical Society of Japan.1992,65(2):392-5.
[30]Delhomel,J.F.;Yous,S.;Depreux,P.;Lesieur,D.Synthesis of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives as potential beta-3-adrenergic receptor ligands[J].Journal of Heterocyclic Chemistry.2001,38(3),633-639.
[31]Gordon,B.;Frederick,C.;John,M.E.;Diane,L..Variation in the Aromatic Ring of Cromakalim:Antihypertensive Activity of Pyranoridines and 6-Alkyl-2H-1-benzopyrans[J].J.Med.Chem.1990,33:3023-3027.
[32]Yu,D.L.;Brossi,A.;Kilgore,N.;Wild,C.;Allaway,G.;Lee,K.H.Anti-HIV agents.Part 55:3'R,4'R-di-(O)-(-)-camphanoyl-2',2'- dimethyldihydropyrano [2,3-f]chromone(DCP),a novel anti-HIV agent[J].Bioorg.Med.Chem.Lett.2003,13(9):1575-1576.
[33]Yu,D.L.;Chin-Ho,C.;Brossi,A.;Lee,K.H.Anti-AIDS agents.60:3'R,4'R-di-(O)-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) as potent anti-HIV agent[J].J.Med.Chem.2004,47:4072-4082.
[34]Asranjaneyulu;Mallavadhani,U.V.;Venkateswarlu,Y.;Ramaprasad,A.V.Reaction of Acetic Anhydride/Zinc Chloride Reagent with Phenols:Improved Yields of Hydroxyacetophenones[J].Indian Journal of Chemistry.1987,26B:823-826.
[35]Gulati,Khusshal C.;Seth,Sant R.;Venkataraman,Krishnasami.Synthetical experiments in the chromone group.ⅩⅢ.Hydroxy-2-styrylchromones[J].Journal of the Chemical Society.1934,1765-7.
[36]Dewick,Paul M.;Martin,Maria.Biosynthesis of pterocarpan,isoflavan and coumestan metabolites of Medicago sativa:chalcone,isoflavone and isoflavanone precursors[J]Phytochemistry.1979,18(4):597-602.
[37]Lakshmi,N.D.;Nitar,C.S.;Asoke,k.A New General Approach for Introducing Side Chain in Coumarins Utilising Bromozinc as Chemo-,Regioand Stereo-selective Reagents[J].Indian J.of Chem.1988,27B:801-805.
[38]Sharan,P.;Girl,S.;Nizamuddin.Synthesis of some 7-Hydroxy-4-methylcoumarin-8-yl Chalcones and related Iso-oxazoles as Potential Funficides[J].J.Indian Chem.1989,66:393-394.
[39]Dean,R.B.;David,K.;Janice,D.F.;Henry,R.Synthesis and Derivitization of 8-Acetylpsoralens.Acetyl Migrations during Claisen Rearrangemeng[J].J.Org.Chem.1983,48:2709-2719.
[40]Takehiko,N.A Novel Transformation of Alcohols to Thiols[J].Journal of the Chemical Society,Chemical Communications.1989,No.4:205-206.
[41]Takehiko,N.Direct Conversion of Alcohols into Thiols[J].J.Chem.Soc.Perkin Trans.,1993,1113-1117.
[1]Kesisis G.;Broxterman H.;Giaccone G..Angiogenesis inhibitors.Drug selectivity and target specificity[J].CURRENT PHARMACEUTICAL DESIGN,2007,13(27):2795-2809.
[2]Emoto M.;Tachibana K.;Iwasaki H.et al.Antitumor effect of TNP-470,an angiogenesis inhibitor,combined with ultrasound irradiation for human uterine sarcoma xenografts evaluated using contrast color Doppler ultrasound[J].CANCER SCIENCE,2007,98(6):929-935.
[3]Thotathil Z.;Jameson M.B.Early experience with novel immunomodulators for cancer treatment[J].EXPERT OPINION ON INVESTIGATIONAL DR UGS,2007,16(9):1391-1403.
[4]Sridhar SS,Shepherd FA,Targeting angiogenesis:a review of angiogenesis inhibitors in the treatment of lung cancer[J].LUNG CANCER,2003,42:S81-S91.
[5]Yokoyama Y.;Ramakrishnan S.;Binding of endostatin to human ovarian cancer cells inhibits cell attachment[J].INTERNATIONAL JOURNAL OF CANCER 2007,121(11):2402-2409.
[6]Ferrara N.VEGF and the quest for tumour angiogenesis factors[J].Nature Reviews,2002,2:7 95-803.
[7]Goodsell D.S.The Molecular Perspective:VEGF and Angiogenesis[J].Oncotogist,2002,7:569-570
[8]刘新云 朱景中 涂自良 陈燕 VEGF受体酪氨酸激酶抑制剂的研究进展.中国药师:2005,8(5):369-371
[9]Laurent F.H.;Andrew P.T.;Craig J.;et al.Design and Structure-Activity Relationship of a New Class of Potent VEGF Receptor Tyrosine Kinase Inhibitors[J].J.Med.Chem.1999,42:5369-5389
[10]Peifer C.;Stoiber,T.;Unger,et al.Design,Synthesis,and Biological Evaluation of 3,4-Diarylmaleimides as Angiogenesis Inhibitors[J].J.Med.Chem.2006;49(4):1271-1281.
[11]Potashman M.H.;Bready J.;Coxon A.et al.Design,synthesis,and evaluation of orally active Benzimidazoles and Benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors[J].J.Med.Chem.50(18): 4351-4373.
[12]Alexander S.K.;Evgueni P.et al.1H-1,2,4-Triazol-3-yl-anilines:Novel Potent Inhibitors of Vascular Endothelial Growth Factor Receptors 1 and 2[J].Chem.Biol.Drug Des.2007,69:331-337.
[13]翟鑫,王玉亚,宫平。以血管内皮生长因子及其受体为靶点的肿瘤血管生成抑制剂的研究进展。中国药物化学杂志,2006,16(1):60-63
[14]Kirkpatrick K.;Ogunkolade W.;Elkak A.et al.The mRNA expression of cyclooxygenase-2(COX-2) and vascular endothelial growth factor(VEGF) in human breast cancer[J].Curt.Med.Res.Opin.2002,18(4):237-241.
[15]Pruthi R.S.;Derksen J.E.;Moore D.A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy[J].BJU Int.2004,93:275-278.
[16]Chauhan,D.;Catley,L.;Hideshima,T..Blood.2002,100(6),2187.
[17]Mabjeesh,N.J.;Escuin D.;LaVallee T.M..Cancer Cell.2003,3,363.
[18]Stafford,S.J.et.al;J.Sung.Res..2005,125,104.
[19]Bradshaw,T.D.;Wrigley,S.;Shi,D.F.British Journal of Cancer,1998,77(5),745.
[20]Geoffrey,W.;Tracey,B.;Patrizia,D.Bioo.Med Chem.Lett.2000,10,513.
[21]James,M.H.;Hollis Showalter,H.D..Pharmacol.Then.1999,82,169.
[22]Bei Na Zhang,king Chen,Qian Zhang,Peng Xia.Some Unreported By-Products From The Reaction Of 1,4-Dien-3-One Steroids With 2-(Methylamino)Benzethiol/BF_3[J].Steroids,70(2),111-116(2005).
[23]Bei Na Zhang,Ying Chen,Qian Zhang,Peng Xia.A concise effective deprotection of spiro 3-cyclic thiaza ketal of steroidal 1,4-dien-3-one[J].Steroids,72(1),60-63(2007).
[24]Hidenori,C.;Shun-ichiro,K.;Nishiki I.Bull.Chem.Soc.Jpn.1989,62,1215.
[25]Mikio,H.;Tadashi,K.;Hiroshi,S.Yakugaku Zasshi,1975,95(6),634.
[26]Citterio,A.;Gentile,A.;Minisci,F.Tetrahedron Letter,1982,23,5587.
[27]Minisci,F.;Vismara,E.;Fonatana,F.J.Org.Chem.1989,54,5224.
[28]Human VEGF Quantitative Reagent Kit.http://www.innogent-cn.com.
[29]VEGF bioactivity detection:The single human breast cancer cell MDA-MB-231 suspension in 1640 Medium with 10%Foetal Bovine Serum at a concentration of 10~4-10~5 cells per milliliter was prepared.Each sample to be detected were resolved in distilled water or 0.5% DMSO and diluted to multipropor on concentration. 90μL cell suspension and 10μL sample solution was mixed and culvitated in each well of 96 well-micro plate at 37℃ with 5% CO_2 for three days. The IC_(50) was obtained by detecting the cell growth inhibitory rate directly using 10μL medium as the blank control. Then the VEFG inhibitory rate was detected using VEGF ELISA kit (SHENZHEN YINUOJIN Biotechnology Company). The EC_(50) was obtained by calculation from the diagram of inhibitory rate v.s. sample concentration.
[30] Dina Chelouche-Lev, Claudia P. Miller, Carmen Tellez. European Journal of Cancer, 2004,40, 2509.
1:De Clercq E.New developments in anti-HIV[J].Biochimica et Biophysica Acta,2002,1587(2):258-275.
2.De Clercq E.New anti-HIV angents and targets[J].Med Res Rev,2002,22(6):5312-5651
3.Moulard M,Lortat-Jacob H,Mondor I,Roca G,Wyatt R,Sodroski J,Zhao L,Olson W,Kwong PD,Sattentau QJ.Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp 120[J].J Virol,2000;74:1948-1960.
4.Luscher-Mattli M.Polyanions-A lost chance in the fight against HIV and other virus diseases[J].Antiviral Chem Chemother 2000;11:249-259.
5.Dragic,T.,Trkola,A.,Thompson,D.A.,Cormier,E.G.,Kajumo,F.A.,Maxwell,E.,Lin,S.W.,Ying,W.,Smith,S.O.,Sakmar,T.P.,Moore,J.P.,A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5[J].Proc.Natl Acad.Sci.U.S.A.2000.97,5639-5644.
6.Yakashima,K.,Miyake,H.,Kanzaki,N.,Yagawa,Y.,Wang,X.,Sugihara,Y.,Iizawa,Y.,Baba,M.,Highly potent inhibition of human immunodeficiency virus type 1replication by YAK-220,an orally bioavailable small-molecule CCR5 antagonist[J].Antimicrob.Agents Chemother 2005.49,3474-3482.
7.Baba,M.,Takashima,K.,Miyake,H.,Kanzaki,N.,Teshima,K.,Wang,X.,Shiraishi,M.,Iizawa,Y.,TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans[J].Antimicrob.Agents Chemother 2005.49,4584-4591.
8.Strizki,J.M.,Tremblay,C.,Xu,S.,Wojcik,L.,Wagner,N.,Gonsiorek,W.,Hipkin,R.W.,Chou,C.C.,Pugliese-Sivo,C.,Xiao,Y.,Tagat,J.R.,Cox,K.,Priestley,T.,Sorota, S., Huang, W., Hirsch, M., Reyes, R.G., Baroudy, B.M., Discovery and characterization of vicriviroc (SCH 417690), A CCR5 antagonist with potent activity against human immunodeficiency virus type 1 [J]. Antimicrob. Agents Chemother. 2005.49, 4911-4919.
9. Dorr, P., Westby, M., Dobbs, S., Griffin, P., Irvine, B., Macartney, M, Mori, J., Rickett, G., Smith-Burchnell, C., Napier, C., Webster, R., Armour, D., Price, D., Stammen, B., Wood, A., Perros, M., Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity [J]. Antimicrob. Agents Chemother. 2005.49,4721-4732.
10. Hatse, S., Princen, K., Bridger, G., De Clercq, E., Schols, D., Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4 [J]. FEBS Lett. 2002.527, 255-262.
11. Labrosse B, Treboute C, Alizon M. Sensitivity to a nonpeptide compound (RPR103611) blocking human immunodeficiency virus type 1 Env-mediated fusion depends on sequence and accessibility of the gp41 loop region [J]. J Virol 2000; 74: 2142-2150.
12. Temiz NA, Bahar I: Inhibitor binding alters the directions of domain motions in HIV-1 reverse transcriptase [J]. Proteins 2002, 49: 61-70.
13. Shen L, Shen J, Luo X, Cheng F, Xu Y, Chen K, Arnold E, Ding J, Jiang H: Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT [J]. Biophys J 2003,84: 3547-3563.
14. Gazzard BG, Pozniak AL, Rosenbaum W, Yeni GP, Staszewski S, Arasteh K, De Dier K, Peeters M, Woodfall B, Stebbing J, vant' Klooster GA: An open-label assessment of TMC 125 a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance [J]. AIDS 2003, 17:49-54.
15. Hammond JN, Raber S, Amantea M, Grettenberger H, Shetty B, Hawley P, Patick AK: Determination of capravirine inhibitory quotient in HIV infected, NNRTI-treatment experienced patients [J]. Abstract 649, 41st Annual Meeting of the American Society of Infectious Diseases: 2003. October 9-12; San Diego.
16. Pauwels R. New non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development for the treatment of HIV infections[J]. Current Opinion in Pharmacology 2004, 4:437-446
17. Pluymers, W., De Clercq, E., and Debyser, Z. HIV-1 inte-gration as a target for antiretroviral therapy: a review. Curr. Drug Targets-Infectious Disorders 2001, 7, 133-149.
18. Pannecouque C., Pluymers W., Maele B. V., Tetz V., Cherepanov P., De Clercq, E., Witvrouw M, Debyser Z. New Class of HIV Integrase Inhibitors that Block Viral Replication in Cell[J]. Culture Current Biology, Vol. 12, 1169-1177, July 23,2002
19. Okamoto H, Cujec TP, Okamoto M, Peterlin BM, Baba M, Okamoto T. Inhibition of the RNA-dependent transactivation and replication of human immunodeficiency virus type 1 by a fluoroquinoline derivative K-37 [J]. Virology 2000;272:402-408.
20. Abdel-Rahman, H. M.; Al-Karamany, G.S.; El-Koussi, N. A.; Youssef, A. F.; Kiso, Y. HIV protease inhibitors: peptidomimetic drugs and future perspectives [J]. Curr. Med. Chem. 2002, 9,1905-1922.
21. Randolph, J. T.; DeGoey, D. A. Peptidomimetic inhibitors of HIV protease [J]. Curr. Top. Med. Chem. 2004, 4, 1079-1095.
22. Rodriguez-Barrios, R; Gago, R HIV protease inhibition: limited recent progress and advances in understanding current pitfalls [J]. Curr. Top. Med. Chem. 2004, 4,991-1007.
23. Bursavich, M. G.; Rich, D. H. Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles [J]. J. Med. Chem. 2002, 45, 541-558.
24. Carr, A. Toxicity of antiretroviral therapy and implications for drug development [J]. Nat. Rev. Drug Discovery 2003,2, 624-634.
25. Wang, R; Ross, J. Atazanavir: a novel azapeptide inhibitor of HIV-1 protease [J]. Formulary 2003,38,691-702.
26. Raja, A.; Lebbos, J.; Kirkpatrick, P. Fresh from the pipeline: Atazanavir sulphate [J]. Nat. Rev. Drug Discovery 2003,2, 857-858.
27. Rusconi S, La Seta Catamancio S, Citterio P, Kurtagic S, Violin M, Balotta C, Moroni M, Galli M, d'Arminio-Monforte A. Susceptibility to PNU-140690 (tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors [J]. Antimicrob Agents Chemother 2000; 44: 1328-1332.
28.Ekegren J.K.,Unge T.,Safa M.Z.,Wallberg H.,Samuelsson B.,Hallberg A.,A New Class of HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimicking Scaffold[J].J.Med.Chem.2005,48,8098-8102.
29.天然来源具有抗HIV活性的多肽和蛋白类化合物。王建华等,中国天然药物。2004年11月第2卷第6期:321-327.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |