|其他摘要||This thesis includes: diversity-oriented synthesis derived from isain and the bioactivity screening of the derivatives. Eight series of isatin derivatives were synthesized, and the bioactivities on antibacterial, antivirus, antitumor and neuroprotection of these compounds were investigated. Meanwhile, the progress of biological study of isatin and its derivatives were reviewed in the thesis.
In the first chapter, a series of compounds was synthesized by Aldol addition with isatin and methyl ketone catalized by diethyl amine. The possible mechanism was also discussed. And the bioactivities on protective effect on the apoptosis of PC12 cells induced by H2O2, cytotoxicity against lung cancer cell line A549 and P388 cell line was screened. These (N-substituted) isatins were showed potent antioxidant activity against H2O2-induced impairment in PC12 cells and cytotoxicity against lung cancer cell line A549 and P388 cell line.
3-hydroxy-3-(2-oxo-propyl)-1,3-dihydro-indol-2-one is a new chemical activator discoveried by our group, which activats plant systemic acquired resistance (SAR). The synthetic method on a large scale was investigated in the second chapter. It was found that inclusion compounds of b-CD with phenyl-substituted amine could catalyse the Aldol condensation of isatin and aceton quckly with high yield, and the catalyst could be reused.
The third chapter described L-proline and its derivatives could catalyze asymmetric Aldol condensation of acetone and isatin / (N-substituted) isatins. The reaction between acetone and (N-substituted) isatins catalized by L-proline was much faster than that of acetone and isatin, presenting the desired products with 30-79% ee. The mechanism of this reaction was also discussed, and it was suggested that a stronger hydrogen bond receptor, as well as a stronger hydrogen bond donor in the transition state, could decrease the energy of the transition state.
In the fourth chapter a series of derivatives of isatin was synthesized by the addition of phenylacetylene to isatin / (N-substituted) isatins promoted by Et2Zn without any employment of specific ligands, and the mechanism was discussed. Most of these compounds showed activities on neuroprotection and cytotoxisities on tumor cell lines(A459, P388).
In the fifth chapter, schiff base derivatives of isatin were synthesized by the condensation of isatin and anilin, hydroxyl amine, hydrazine and thiosemicarbazide, forther more, mannich base derivatives were synthesized by the reaction of the schiff base compounds, formaldehydes and secondary amines. The schiff bases derived from isatin and anilin analogies showed potent activities on neuroprotection and cytotoxisities on tumor cell lines (A459, P388), and the mannich bases showed potent activities on anti- Magnaporthe grisea.
In the sixth chapter a series of 3-methylene-indol-2-one derivatives was synthesized. During the bioactive screen four 3-aryl-methylene-indol-2-one derivatives showed potent activities on inhibition of caspase-3; three 3-phenyl-methylene-indol-2-one derivatives showed potent antioxidant activities against H2O2-induced impairment in PC12 cells; and almost all of the 3-aryl-methylene-indol-2-one derivatives showed potent cytotoxisities on antitumor (A459, P388), while the 3-nitro-methylene-indol- 2-one with low activity in three aspects.
In the seventh chapter, a series of spiro [pyrrolidine-2, 3’-oxindole] derivatives was synthesized by the 1, 3-dipolar-addition reaction of isatin / (N-substituted) isatins, α-amino acids and (E)-β-aryl-nitroolefins. The reactions were in good yields, affording two regioisomers and the regioselectivties and the reaction results were different from the previous reported spiro [pyrrolidine 2, 3’- oxindole] derivatives. The primary bioactive screenings were showed that almost all of the compounds could protect the PC12 cells of H2O2-induced impairment, and some of them had capacities against tumor cell lines (A459, P388). Among them, compound 95 could inhibit the two cells at a higher level under the concentration of 10-5M.
In the eighth chapter, another series of spiro [pyrrolidine-2, 3’-oxindole] derivatives was synthesized by the 1, 3-dipolar-addition reaction of isatin / (N-substituted) isatins, α-amino acids and (E)-2-acyl-styrene to investigate the regioselectvity of this reaction, and it was found that all of the reactions had the same regioselectvity as the reaction of isatin, α-amino acids and chalcone, but different from the reaction described in chapter seven. The primary bioactivities screen showed no compound could protect the PC12 cell for H2O2-induced impairment. However, some of the compounds showed activities against tumor cell lines (A459, P388).
Based on the different regioselectivity in the reactions discribed in chapter seven and eight, the mechanism was studied associated with caculation of B3LYP/6-31G(d) in chapter nine. A new mechanism was suggested: a π-π stack controlling in the transition state might determine the regioselectivity in the reactions. This mechanism could explain the regioselectivity reasonably.
In the tenth chapter, the inhibition abilities of all these compounds against SARS coronavirus 3C-like protease was screened, and many compounds exhibited potent inhibition for the protease. The possible interaction between different kinds of compounds and the substrate-binding pocket of the protean was also discussed. The results suggested that 1,2-dicarbonyl, Micheal acceptor and nitro group were of importance for the inhibition.
The the eleventh chapter reviewed the progress of biological study of isatin and its derivatives.|