摘要
本论文根据鱼藤酮及其衍生物的构效关系并结合抗抑郁药物以及抗肿瘤药物的研究成果,设计合成一系列新颖的鱼藤酮衍生物,并对所合成的化合物进行体外活性评价,为鱼藤酮的应用以及活性的多样性研究打下基础。
本论文研究工作分为三个部分：
1.本研究以鱼藤酮为起始原料,在强碱条件下经氧硫叶立德开环重排,引入环丙结构到鱼藤酮分子中,并对活性部位进行醚化和酯化结构修饰,设计合成了12个结构新颖的环丙鱼藤衍生物；采用活性亚结构拼接原理,引入具有较好生物活性的肟醚结构到化合物3a分子中,设计合成了5个环丙鱼藤肟醚衍生物；通过酰氯催化的贝克曼重排反应得到结构新颖的环丙鱼藤酰胺化合物7。化合物经1H NMR和MS对结构进行了确证。培养了关键中间体2和目标化合物7的晶体结构,经X-射线衍射分析表明得到化合物的分子与预期化合物结构一致。由于氧硫叶立德可以从两个方向进攻鱼藤酮分子,因此形成的环丙烷结构在分子中存在两种构象,单晶结构显示一个晶胞中同时存在环丙鱼藤衍生物的一对非对映异构体。
通过高通量筛选方法测试了化合物的杀虫、杀菌和除草活性,结果显示该系列化合物具有一定的杀虫活性。
2.以鱼藤酮为原料,与水合肼进行开环重排反应引入具有5-HT重摄取/5-HTlA受体双重抑制作用药物的碱性中心吡唑环结构到鱼藤酮分子中,并对分子的胺基以及酚羟基进行醚化以及酯化结构修饰得到12个结构新颖的鱼藤吡唑衍生物；其中化合物10d和10e通过亲核取代反应引入不同的杂原子侧链,设计合成了28个N-酰基吡唑鱼藤酚化合物。化合物经1HNMR、13C NMR和MS对结构进行了确证。培养了化合物lla的晶体结构,经X-射线衍射分析进一步确证了化合物结构。由于水合肼的氨基可以从两个方向进攻鱼藤酮分子,因此形成的吡唑环结构在分子中存在两种构象,单晶显示一个晶胞中同时存在鱼藤吡唑化合物的一对非对映异构体。
通过建立荧光物质ASP的高通量筛选手段测试了化合物对5-HT重摄取的抑制活性,结果显示大部分化合物生物活性较好。
3.以取代苯酚为原料通过亲核取代、环合、溴代、缩酮化、重排以及水解反应构建了鱼藤酮的苯并吡喃结构基团,并以商业化的具有较好生物活性的呋喃酚替代鱼藤酮的2-异丙烯基苯并呋喃结构基团,以酰胺基团代替鱼藤酮的二氢吡喃连接基团将苯并吡喃以及苯并呋喃结构以一定构型相连接,得到具有新颖结构的三个系列共28个化合物。
所得化合物经1H NMR和MS对结构进行了确证,并测试了该类化合物对Hel细胞的体外抑制活性,结果表明该系列化合物具有较好的抑制活性。
Rotenone is a broad-spectrum insecticide and its derivatives show several biological activities including acaricide and antitumor. Based on the structure-activity relationship of rotenone derivatives and the research of antidepressant drugs and anticancer drugs, we designed and synthesized a series of novel rotenone derivatives, and evaluated their bioactivities in vitro. The main results of this thesis are described as followings:
1. Twelve novel cyclopropane rotenone derivatives were designed and synthesized from rotenone by open-loop rearrangement with the dimethyloxo-sulphonium methylide in alkaline conditions, etherification and esterification to modify the structure of active sites. Five cycloprop rotenone oxime-ether derivatives were designed and synthesized by the principle of Substructure Link Way, introducing the oxime-ethers group with excellent bioacitivity into the compound3a. The novel compound7was obtained by Beckmann rearrangement reaction with chloride-catalyzed.
The structures of new compounds were characterized by1H NMR and MS. For the key intermediates, we analysis the crystal structures of compound2and7by X-ray diffraction, which were consistent with the target compound. Owing to the attack of rotenone by dimethyloxosulphonium methylide from two directions, there are two conformations of cyclopropane structure in the molecule. X-ray diffraction shows that a pair of diastereoisomers exists in the crystal lattice of cycloprop rotenone.
The bioassay indicated that some compounds show moderate insecticidal activity.
2. Twelve pyrazole rotenone derivatives were designed and synthesized from rotenone via the open-loop rearrangement react with hydrazine hydrate to introduce an alkaline center of pyrazole ring as a dual inhibitors, the etherification of amine group and esterification of phenolic hydroxyl group. Twenty-eight N-acylpyrazole rotenone derivatives were designed and synthesized from the compound10d and10e by the nucleophilic substitution reaction to introduce different side chains of hetero atoms.
The structures of newly compounds were confirmed by1H NMR,13C NMR and MS. We obtained the crystal structure of compound11a, which was consistent with the target compound by X-ray diffraction analysis. For the amino group of the hydrazine hydrate offensing rotenone molecule from two directions, there were two conformations of pyrazole structure present in the molecule. X-ray diffraction found that a pair of diastereoisomers existed in one crystal lattice of pyrazole rotenone.
Through the high-throughput screening means of fluorescent substance ASP, the compounds were evaluated for their activity as5-HT inhibitor in vitro. Most of the compound exhibited potent inhibitory activity against5-HT.
3. In order to establish a certain configuration between benzopyran and benzofuran, three series of twenty-eight compounds were designed and synthesized from the substituted phenol by nucleophilic substitution, cyclization, bromation, ketalization, rearrangement and hydrolysis reaction, then altered2-isopropenyl benzofuran group of rotenone with benzofuranol, which has preferred biological activity to commercialize, and finally altered dihydropyran group with amide group.
The structures of novel compounds were determined by1H NMR and MS. The antitumor assay indicated that this series of compounds have a certain degree of antitumor activity against Hela cell line.
引文
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