【作者】 石继仙；

【导师】 赵康；

【作者基本信息】 天津大学 ， 应用化学， 2005， 博士

【摘要】 微管是成功治疗肿瘤的药物靶点之一,在维持和发展细胞形态、细胞内物质运输、细胞内信号传导、细胞分裂等方面发挥重要作用。以微管为靶点的药物,既可引起微管功能障碍和细胞凋亡;又可作为肿瘤血管阻断剂,阻断血管对肿瘤的营养供给。以微管为作用靶点的现有药物按其结合位点分为3类:长春花生物碱类、紫杉醇类及秋水仙碱类。前两类均来自天然产物或其衍生物,固有的大分子结构使得难以全合成,且副作用较大。因此,化学结构相对简单的秋水仙碱及其类似物引起人们的广泛关注。本文主要对以下几个方面的工作进行了研究:1.对已知的秋水仙碱结合位点的微管微丝抑制剂进行SAR研究,设计了含有不同特征取代基的三个系列的多取代杂芳环化合物。2.以邻溴苯酚为原料,经历O-烷基化、傅氏酰基化、羰基化合物α-卤代反应,得到α-溴代芳酮化合物;以不同烷氧基取代的苯甲醛为原料,经历与溴乙烷格氏试剂反应、Jone’s氧化反应得到芳酮化合物;再与另一分子α-溴代芳酮两两偶联,共合成8个重要1,4-二芳基-2,3-二甲基-1,4-丁二酮中间体。3.以1,4-二芳基-2,3-二甲基-1,4-丁二酮为原料,分别与氯化氢的干燥甲醇溶液、Lawesson试剂、乙酸铵、甲胺/冰醋酸或正丁胺/冰醋酸在一定的条件下脱水环化,发生Paal-Knorr反应而得到2,5-二芳基-3,4-二甲基呋喃、噻吩、吡咯及N-烷基吡咯化合物。共合成39个多取代的杂芳环目标物,其中37个为未见文献报道的新化合物,其结构经核磁共振氢谱和碳谱确证。4.以多取代杂环化合物为原料,在催化剂PdCl2(dppf)、配体DPPF及碱t-BuONa作用下,与各种取代胺(脂肪伯胺、脂肪仲胺、芳香伯胺及EDG-芳香伯胺)发生偶联反应而得到含有不同取代胺基的多取代杂环目标物。共合成了38个不同取代胺修饰的多取代杂芳环目标物,均为未见文献报道的新化合物,结构经核磁共振氢谱和碳谱确证,并选取目标物112进行X-射线衍射分析,得到了晶体结构的数据。5.对所合成的目标物进行初步生物活性评价。对体外人乳腺癌MCF-7细胞株的抗肿瘤试验发现个别化合物活性几乎与紫杉醇相当;对人PBM(外周血单核细胞)的抗HIV-1及细胞毒性试验发现所设计的化合物具有一定的抗HIV-1活性,且细胞毒性较小。更多还原

【Abstract】 Microtubules are among the most successful targets for cancer chemotherapy.They are important in many cellular processes such as the development andmaintenance of cell shape, transport of components through cells, cell signaltransduction, and cell division. Microtubule-targeted drugs can lead to mitotic blockand cell apoptosis, and some also can act as vascular-targeting agents, depolymerizingmicrotubules of newly formed vascular to shut down the blood supply to tumours.The microtubule-targeted antimitotic drugs are usually classified into three maingroups, Vinca alkaloids, paclitaxels, and colchicines domain. The Vinca alkaloids andpaclitaxels, which are first isolated from natural plants, are difficult to obtain by totalsynthesis as well as their serious side effects of neurotoxicity and myelosuppression.As a result, colchicines and its analogues have generated considerable interest due tosimple and small molecule structure. The work following has been carried out in thispaper.1.The development and SAR of microtubule-targeted agents that bind to colchicinesdomain are reviewed and three series of target compounds with differentsubstituted groups are designed.2.o-Bromophenol was alkylated by alkyl halides followed via acylation withpropionyl chloride and bromination with bromine in refluxing chloroform toafford α-bromoaromatic ketone;Multi-alkoxybenzaldehydes were treated withGrignard reagent from bromoethane, then oxidized with Jone’s reagent to givearomatic ketone. Deprotonation of aromatic ketone by sodium amide in liquidammonia and consequent alkylation with α-bromoaromatic ketone produce thekey intermediates for target compounds——1,4-diaryl-2,3-dimethyl-1,4-butane-diones.3.Diketones were treated with diverse cyclization reagents under different reactionconditions to afford multi-substituted heterocyclic compounds. 1,4-Dicarbonylswere cyclized to multi-substituted furans, thiophenes, pyrroles or N-alkyl pyrrolesupon their treatment with hydrochloric acid/methanol solution in dichloromethane,Lawesson reagent, ammonium acetate or alkyl amine/acetic acid, respectively.Thirty-nine target heterocycles were obtained and thirty-seven of them are newcompounds. The target compounds were confirmed by 1HNMR and 13CNMR.4.Multi-substituted heterocyclic compounds were converted to correspondingamine-containing target compounds with diverse substituted amines via thepalladium-catalyzed coupling reaction under the catalyst of PdCl2(dppf), theligand of DPPF, and the base of t-BuONa. Amines, including alkyl amines(methylamine, n-propylamine, n-butylamine, and benzylamine), secondary amines(N,N-diethylamine, pyrroline, piperidine, and morpholine), aromatic amines(aniline, 4-methylaniline, 4-methoxyaniline, and 4-chloroaniline), andEDG-anilines (2-methoxyaniline, 4-ethoxyaniline, 3,4-dimethoxy aniline,3,4,5-trimethoxyaniline, and 4-benzyloxyaniline), were reacted withbromine-containing heterocycle compounds to give thirty-eight novelamine-containing heterocycle compounds, which were confirmed by 1HNMR and13CNMR. The compound 112 was also identified by X-ray crystallography.5.Some of target compounds were evaluated their anticancer and antiviral activitiesin vitro. Several heterocycle compounds showed good and potent inhibition toMCF-7 and one of them was found to be almost identical activity to paclitaxel.Several compounds were found possessing certain anti-HIV-1 efficacy as well aslow cytotoxciities.更多还原