Synthesis And Antitumor Activity Of The Derivatives Of Novel Xanthenes And Furan

Anthraquinone drugs are very important antitumor medicines, which exhibit the advantages of wide antitumor spectrum and good clinical practice. Some anthraquinone compounds including doxorubicin, daunorubicin, doxorubicin and mitoxantrone are widely used as antitumor drugs clinically. However, these drugs may lead to bone marrow suppression, cardiac toxicity and other side effects as the dose increases to a relatively high level. Therefore, it is of significance to design analogues of anthraquinone with less toxicity.As an analogue of xanthenes, Dactinomycin D is an excellent antitumor drug, and it is found from literature that the toxicity of anthraquinone compound to the heart can be reduced by replacing the carbonyl group with oxygen atom with the antitumor activity kept unchanged, so it is of great importance to design new types of xanthenes derivatives. In this thesis,162target compounds including130dibenzo[a,j]xanthenes compounds and32dinaphtho[2,1-b:1’.2’-d]furan derivatives were designed and synthesized, according to the structure of dactinomycin D. And the structures of all the compounds were characterized and identified by1H NMR,13C NMR, HR-MS and IR spectra. Using As2O3as the positive control, antitumor activities of91representative compounds were evaluated on carcinoma cell lines (SK-HEP-1, HepG2and SMMC-7721cells), acute promyelocytic leukemia NB4cells and uterine cervix cancer HeLa cells.Among130dibenzene[a,j]xanthenes compounds, there are117new compounds and13known compounds, and all the known derivatives were prepared by solvent-free green synthesis method.32derivatives of furan include seventeen6,8-disubstituted dinaphtho[2,1-b:1’,2’-d]furan compounds, fourteen3,11-disubstituted dinaphtho[2,1-b:1’,2’-d]furan derivatives and one parent compound dinaphtho[2,1-b:1’,2’-d]furan. Among these32compounds, there are twenty-eight new compounds and four known compounds.Through the study on the antitumor activities of dibenzo[aj]xanthenes compounds, the following conclusions can be drawn:(1) Antitumor activities of the parent compounds can be significantly enhanced after3and11positions of the compounds are substituted with proper groups;(2) As only an alkyl group is introduced on the N3(N11) atoms, antitumor activities decrease with the increasing of the size of the alkyl group;(3) When two alkyl groups are introduced on the N3(N11) atoms, the antitumor activities of diethyl derivatives are stronger than those of dimethyl ones;(4) When14position is substituted with p-halophenyl groups, the antitumor activity of the derivatives is the strongest, However, when14position is substituted with o-halophenyl groups, the antitumor activity become weaker;(5) The antitumor activities of these compounds may be affected by substituent groups on3,11and14positions synergistically. The IC50values of compounds35,37,30,31and32for NB4cell are0.82,0.96,3.08,4.12and4.01μM, respectively. Their IC50values are less than5.01μM of positive drug As2O3, deserving to be studied furtherly.Through the study on the antitumor activities of6,8-disubstituted dinaphtho[2,1-b:1’,2’-d]furan, it is found that compounds154,155,159and162have stronger inhibitive effects on tumor cells and their IC50values are less than20μM (the IC50value of the parent compound148exceeds50μM). The results show that antitumor activities of this kind of compounds can be enhanced when6and8positions are substituted.Through the study on the antitumor activities of3,11-disubstituted dinaphtho[2,1-b:1’,2’-d|furan derivatives, it is found that the IC50value of compound161is0.57μM for SMMC-7721cell, which is less than9.13μM of positive drug As2O3. In addition, the IC50value of compound178also reaches5.07μM for NB4cell. Further investigations need to be carried out on the antitumor activities of the two compounds. The results indicate that the antitumor activities of dinaphtho[2,1-b:1’,2’-d]furan compound148can be improved obviously when3and11positions are properly substituted.Taking compounds37and38as the representative compounds with better antitumor activities, the mechanism of inhibiting on HeLa cell was studied by the flow cytometry analysis method in this thesis. The results show that the inhibitory effects of compounds37and38on tumor cells are realized mainly by inducing cell apoptosis.