Design,Synthesis And Preliminary Antitumor Activities Evaluation Of New Tricyclic Scaffolds Derivative Hydroxamic Acids

This dissertation mainly focused on the design, synthesis and preliminary biological evaluation of potential anti-tumor active tricyclic scaffolds hydroxamic acid based histone deacetylase inhibitors (HDACi). We also did some researches on Beckmann rearrangement and its application.1. Design, synthesis and preliminary biological evaluation of tetrahydron-y-carboline derivative hydroxamic acids as novel histone deacetylase inhibitorsThe Fischer reaction was applied to construct 8-Bromo substituted tetrahydro-y-carboline, then R1 group at N2 position were changed with different benzyl, benzoyl, sulfonyl, saturated or unsaturated alkyl groups. The N5 position were substituted with various length chains that were substituted with dimethylamine, diethylamine, piperidine, morpholine and pyrroline.35 tetrahydron-y-carboline derivative hydroxamic acids were obtained for biological evaluation via ten steps according to the computer aided drug design and known pharmacophore model.The tetrahydron-y-carboline derivative compounds showed good activities against HDACs and HDACl isotype in vitro. Most of the compounds showed similar, or in some cases even more potent antitumor activities to inhibit cancer cell growth on different tumor cell lines than the positive control SAHA. Representative compounds selectited for more in-tensive research had showed that they can lead to the accumulation of acetylated histones and up-regulation of p21WAF/CIPI, influence cell cycle progression and induce apoptosis. Com-poundsⅡ-10a exhibited excellent in vivo anticancer activities in human Lewis lung cancer xenograft model using SAHA as positive control. No significant body weight difference among the groups of mice and no signs of overt toxicity were observed during the treatment. To identify the structural features of the active molecules bonding to protein, We docked compoundⅡ-10a into the HDACI homology model based on HDLP and HDAC8 revealed a key electrostatic interaction between the basic N atom on the N5 substitution and Asp99 ami-no-acid residue. The-CONHOH group chelates the zinc ion at the active site in a bidentate fashion. The amino-acid residues of Phe205 and Phe150 haveπ-πconjugated interaction with the Ph ring in the scaffold of tetrahydron-y-carboline.Taken together, our results indicate thatⅡ-10a exerts an anti-tumor activity in vitro and in vivo and is a promising candidate for further study. Our current findings support that tetra-hydron-y-carboline bearing hydroxamate moiety is valuable in identifying potential cancer therapies. All of these discoveries provide a beneficial theoretical basis for the optimization of leading compound and lay a solid foundation for the discovery of novel more potent HDACi in future.2. Design, synthesis and preliminary biological evaluation of Tetrahydrocarbazole de-rivative hydroxamic acids as novel histone deacetylase inhibitors Seven Tetrahydrocarbazole derivative hydroxamic acids were prepared using 6-bromo-2, 3,4,9-tetrahydro-1H-carbazol-l-one as starting material. The compound 111-25 that was pre-pared by Knoevenagel reaction and compound 111-32 that was prepared by Beckmann reac-tion enjoyed good activities against HCT116 and Hela cell lines, with IC50 values about 5μM. These two leading compounds owed the potential for further study and more potent HDACi may be obtained by introducing suitble substitutes.3. Beckmann rearrangement and its application:We developed a highly efficient catalytic system for Beckmann rearrangement:alumi-num chloride has been found to smoothly promote the Beckmann rearrangement of various ketoximes to the corresponding amides (up to 99% of yield) with 10 mol% catalyst loading in anhydrous acetonitrile under reflux temperature. The procedure offers several advantages including good yields, short reaction times, easily and cheaply obtained catalyst, and simple experimental isolation procedures.In addition, We have developed a facile one-pot strategy for synthesis of N-Substituted thioamides via TsCl-Mediated Beckmann rearrangement of ketoximes. This practical proce-dures provide a straightforward and environmentally benign process for the synthesis of thi-oamides without using odor, and instability thioreagent.