The Synthesis,Structure,Antioxidant And Antitumor Of Organoselenium Compounds

Organoselenium compounds have been paid extensive attention by scientists owing to high activity, low toxicity, and good biocompatibility. In this paper, we investigated the antioxidant activity of major Se-containing- and S-containing compounds in selenium-enriched garlic and inferred that selenium enriched garlic may have the stronger biological activity than ordinary one; based on the structure-activity relationship of diselenide compounds, we clarified that the polarization was an important factor to affect the biological activity of these bioactivities; in addition, we obtained a series of organoselenium including more than 20 new compounds by optimizing synthesis method, and found that two compounds had significant antitumor activity, and revealed the possible mechanism of antitumor. Our study contributed to the understanding of natural organic selenium compounds with biological activities, and provided a new choice for the development of anticancer therapeutics agent with high selectivity. 1) We investigated the DPPH free radical scavenging ability of allitridin, allicin and Se-Allitridin, and found that antioxidant capacity of allicin was the strongest, Se-allitridin was the second, allitridin was the weakest. It found that Se-allitridin has less C-H dissociation enthalpy and ionization potential, but slightly larger electron affinity than allitridin by calculating C-H dissociation enthalpies and ionization potential and electron affinity of the above-mentioned three compounds at the 6-311+G(D, P) level of theory in the gas phase, reflecting Se-allitridin with the stronger ability to scaveng free radicals than allitridin from either extracting hydrogen or electron transfer mechanism considerations. Decomposition barriers of allicin and Se-allicin was determined as 67.0, 63.0 k J/mol respectively by calculating the energy differences between their optimizing configuration and the corresponding transition states, which explained why Se-allicin was difficult to obtain. 2) Six diselenide compounds were synthesized, in which two compounds have not been reported in literature. A preliminary study on the inhibitory effect of six diselenide compounds on Hep G2, Hela and L02 cell was carried out by MTT method. These compounds were able to inhibit the growth of tumor cells in different degrees, in which the inhibitory activity of compound III-2 on Hela cells is the best with the IC50 value at 2.9 g/m L, exhibiting good potential for application. The key effect of selenium atoms in molecules on the bioactivity of their compounds was clarified by calculating atom charge, electrostatic potential, frontier orbital, dipole moments, and polarizability of these compounds at the B3LYP/6-311G*(d) level of theory in the gas phase. Through the correlation analysis, it found that polarization of the compounds with antitumor activity presented the linear correlation, providing a theoretical basis for the further optimization of the molecular structure. 3) The post processing in selenium azole derivatives synthesis is cumbersome and catalyst recycling after reaction was difficult until now. Aiming at these questions, copper catalyst supported by carbon was prepared and used to one pot synthesis of 16 benzene selenium azole compounds including 6 new compounds. With morpholine and adjacent bromine different selenium cyanate ester as reaction template, the paper systematically discussed the influences of reaction temperature, reaction time, reaction solvent, base on the reaction, and obtained the optimized condition. Preparation conditions of activated copper catalyst supported by carbonwere investigated to obtain the best preparation process of catalyst. SEM and XRD were employed to characterize the structure and composition of catalyst, identifying that Cu+ ion was the active component of the catalyst and providing theory basis for catalyst preparation and optimization. 4) Seven selenazolopyridine derivatives were designed and synthesized, in which six compounds were synthesized for the first time. Their in vitro anticancer activities were tested and the result showed that 2-(phenylamino) selenazolo [5,4-b] pyridine(PSe D, compound V-7) can highly inhibit human breast carcinoma MCF-7 cells, has low toxicity to an normal cell line L02. Compound V-7 can result in the increase of the proportion of apoptotic cells expressed a dose-dependent reflected by the Sub-G1 cell population, but no significant change of the S phase population, which referred that V-7 compound induce the apoptosis of MCF-7 cells. Further investigation on the intracellular mechanisms demonstrated that PSe D had a capability to scavenge intracellular reactive oxygen species(ROS) with the result of cell apoptosis. More potential drug for the treatment of tumor will be discovered through the further optimization of selenazolopyridine derivatives. 5) A novel series of methylene carbamimidoselenoate derivatives have been designed, synthesize and well characterized. Firstly the synthesized compounds(VI-1-VI-8) were screened against a panel of five cell lines to evaluate their in vitro anticancer activity by MTT assay. Compound VI-8 was distinguished from other compounds, which had a highest growth inhibitory effect on cancer cells, especially on human cervical cancer He La cells. Compound VI-8 was monitored to enter the cancer cells by targeting lysosome with high cellular uptake potency by fluorescence imaging technique. It confirmed that dynasore-mediated lipid raft endocytosis was mainly involved in the internalization of VI-8 in He La cells. Further investigation on intracellular mechanisms revealed that compound VI-8 was able to cause apoptosis in cancer cells by inducing mitochondrial dysfunction, with an elevated expression of phosphorylated p53. On the basis of these results, we suggests this novel series of organoselenium compounds synthesized may be candidates for further research as a kind of chemotherapeutic agents for cancer therapy.