Research On Synthesis And Biological Activity Of Novel Diselenides,Selenides Compounds

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.