【作者】 赵立伟；

【导师】 李忠； Thomas Wirth；

【作者基本信息】 华东理工大学 ， 应用化学， 2012， 博士

【摘要】 本论文围绕硒元素的性质,设计和合成了5个系列新颖的二硒醚或硒醚类化合物。按其用途分为两类：一是设计新型的手性二硒醚类化合物,转化成硒亲电试剂,研究其在不对称反应中的应用。二是应用硒元素作为硫元素的生物电子等排体,合成含硫抗肿瘤化合物的硒类似物,研究它们的生物活性。第一部分设计和合成了三个新颖的手性醚类二硒醚,以苯酚类化合物为起始原料,通过Mitsunobu反应引入乳酸乙酯作为手性源,经过还原、醚化、邻位锂化、硒化等反应,得到了手性二硒醚。这类二硒醚在二氯甲烷中进行苯乙烯及其衍生物的甲氧化硒化反应,其中C2对称的二硒醚2Vc表现了良好的效果,产物的产率为68%,非对映异构体比例dr高达94：6。并且研究了在不同的苯乙烯衍生物和不同种类的醇作为亲核试剂时的反应情况。第二部分设计和合成了四个新颖的手性酯类二硒醚,以二(2-羟基苯基)二硒醚作为起始原料,通过Mitsunobu反应引入乳酸酯类分子作为手性侧链,以80%左右产率一步反应得到了二硒醚。二硒醚3Ⅵb诱导的苯乙烯的甲氧化硒化反应中,产物的产率为62%,非对映异构体比例dr高达93：7。第三部分设计和合成了四个手性三蝶烯类化合物,首次合成了三蝶烯中心桥头位置9位卤化的不对称分子,并研究了这类化合物的硒化反应。通过氯化铜或N-氯代丁二酰亚胺在蒽类化合物的9位氯化,这类氯化蒽衍生物可以和原位生成的2,5-二甲氧基苯炔迅速进行Diels-Alder反应生成手性三蝶烯。9-氯代三蝶烯衍生物在丁基锂的作用下发生卤锂交换反应,但生成的碳负离子受周围基团的位阻效应的影响阻碍了硒化反应的进行,当位阻效应较小时,可以得到硒醚4Ⅴe’,并且可以通过手性HPLC分析。第四部分合成了七个Bcl-2蛋白的抑制剂5-1的硒醚类似物及衍生物。抗肿瘤细胞活性测试表明,化合物Ia的活性并不如5-1,以Hela细胞为例,仅为其1/85。虚拟分子叠合发现,5Ⅰa的C-Se-C键角小于C-S-C的键角,且C-Se键长略大于C-S键长,另一方面,与二价硫醚中的硫原子相比,硒醚中硒原子形成氢键的能力要弱,这也是影响活性的因素。在这些衍生物中,含有苯硒基基团的化合物5Ⅰd显示了对K562细胞抑制活性,其IC50为12.4μM,同时这类衍生物对K562细胞的抑制能力要优于其他细胞。第五部分应用硒元素具有防治肿瘤和为氧、硫元素的生物电子等排体的性质,研究了向萘酰亚胺引入硒官能团的合成方法,合成了十个具有抗癌活性的含硫萘酰亚胺类化合物的硒取代物,抗肿瘤活性测试显示这类化合物具有中等强度的活性,IC50值在10-6-10-5M。通过紫外和荧光光谱研究与ctDNA嵌入性质,化合物6-17和硒化合物6Ⅲa具有类似的性质,并且也表现了相似的中等程度的抗肿瘤活性。苯基硒醚化合物中,萘酰亚胺上N原子的取代基对活性的影响较大,当取代基为N,N-二乙基乙胺时,活性表现最好,苯基上的取代基修饰效果并不明显。另外这类硒醚化合物显示对K562细胞的活性最强,并且这类化合物能够调节K562细胞的活性氧族(ROS)水平,造成RO水平先下降后升高,诱导K562细胞凋亡。更多还原

【Abstract】 This dissertation is mainly focus on the properties of selenium element, design and synthesis of 5 series novel diselenides and selenides. The application of these compounds can be classified as chiral selenium electrophiles in stereoselective functionalization of alkenes, and as anticancer agents for selenium was bioisosteric element of sulfur.The first part:Three novel chiral diselenides with chiral ether were designed and synthesized. Started from phenol derivatives, after Mitsunobu reaction, reduction, etherification, ortho-Lithiation and selenation, these diselenides were prepared in an efficient synthesis. Methoxyselenenylation of styrene were successful when these diselenides were transferred to electrophile in dichloromethane, and among these diselenides, the C2-symmetric chiral diselenide 2Vc showed the highest selectivity, and yield was 68%, and the diastereomeric ratios (dr) was up to 94:6. The influence of different nucleophiles and different alkenes on the outcome of the selenenylation reaction was studied.The second part:Four new diselenides have been synthesized in one step from bis(2-hydroxyphenyl) diselenide with ester moieties as substituents of a stereogenic center, after Mitsunobu reaction. The selenium electrophile, generated from diselenide 3VIb had been successfully applied in methoxyselenenylation reactions with 62% yield and the diastereomeric ratios (dr) was up to 93:7.The third part:We designed and synthesized four chiral triptycene derivatives. These compounds consist of three different benzene rings tightly connected together at the bridgehead carbon atoms, and the 9-position was chloridized.9-chloro-anthracene derivatives were prepated from anthtacenes chloridized with CuCl2 or NCS. Diels-Alder reaction was the key reaction to form the triptycene scaffold, both benzoquinon and aryne were studied as dienphile. Lithiation were going well when treated these 9-chloro-triptycenes with butyl lithium, but the formed lithium compounds were difficult to selenized and could be ascribed to steric hindrance induced by substituents. One selenide 4V e’ was prepared when steric hindrance is less, and this selenide could be separated by chiral HPLC techniques.The fouth part:Seven selenium analogues of Bcl2 protein family inhibitor 5-1 (8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile) were synthesized, and their anticancer activities were tested. Biological evaluation demonstrated that compound I a was obviously a much less potent cytotoxin compared with 5-1, e.g. about 85-fold less active against Hela cells. The disparity between 5 I a and 5-1 might be attributable to the longer carbon-selenium bond length and smaller selenium-carbon-selenium bond angle, and the poorer ability of the divalent selenium atom (relative to sulfur) to act as a hydrogen bond acceptor in the active site. But in these selenide derivatives, compound 5 I d had antiproliferative activity agaist K562 cell, with IC50 values of 12.4μM.The fifth part:A series of selenium analogues of two known sulfur compounds were synthesized, synthesis method was also studied and their anticancer activities were tested. The preliminary results shown that most of the compounds have moderate anticancer activities with the IC50 values of 10-6-10-5M. The selenide compound 6111a nearly had similar activity with its sulfur analogue 6-17. The DNA-binding study showed the two compounds had similar interaction with ct-DNA by using spectroscopic technique. The primary modification of the substitution in benzene ring was less successful, but the side chain on naphthalimide had notable effect, compound 6Ⅲe had a basic side chain with N,N-diethylamine and showed a little better activity than compound 6Ⅲa. More importantly, same with the fouth part, these selenide compounds exhibited stronger anticancer activities against K562 cell than others tested, and some compounds could adjust the reactive oxygen species (ROS) level in K562 cell, and induced apoptosis.更多还原