【作者】 宋永彬；

【导师】 刘波；

【作者基本信息】 哈尔滨理工大学 ， 材料学， 2013， 博士

【摘要】 蒽醌类药物是非常重要的一类抗肿瘤药物,具有抗瘤谱广,临床疗效好等优点。其中,多柔比星、柔红霉素、表柔比星和米托蒽醌等蒽醌类化合物都是临床上常用抗肿瘤药,但此类药物随着剂量的增加,伴有骨髓抑制、心脏毒性等副作用。因此,以降毒增效为目的的蒽醌类似物的研究工作具有重要意义。抗肿瘤药物放线菌素D是氧杂蒽类似物,具有非常好的临床疗效,通过文献调研又发现以氧原子替代蒽醌结构中的羰基可以降低其对心脏的毒性,并保留其抗肿瘤活性,所以研究新型氧杂蒽类衍生物有重要意义。本论文以放线菌素D为参照物,设计、合成了162个目标化合物,其中二苯[a,j]氧杂蒽类化合物130个,二萘并[2,1-b：1’,2’-d]呋喃衍生物32个,经IR、1H NMR、13C NMR和HR-MS等波谱学方法确认了162个目标化合物的结构。以As203作为阳性对照药,利用MTT法测定了其中91个具有代表性化合物对人肝癌细胞(SK-HEP-1细胞,HepG2细胞,SMMC-7721),人急性早幼粒白血病细胞(NB4细胞),人宫颈癌细胞(HeLa细胞)等5种肿瘤细胞的抗肿瘤活性。在130个二苯[a,j]氧杂蒽类化合物中,共有117个新化合物和13个已知化合物,对于以上13个已知化合物均采用无溶剂的绿色合成方法进行制备。32个二萘并[2,1-b：1’,2’-d]呋喃衍生物分别为17个6,8-二取代二萘并[2,1-b：1’,2’-d]呋喃类化合物,14个3,11-二取代二萘并[2,1-b：1’,2’-d]呋喃类化合物和1个二萘并[2,1-b：1’,2’-d]呋喃母体化合物,这32个化合物中,28个为新化合物,4个为已知化合物。对二苯[a,j]氧杂蒽类化合物的抗肿瘤活性研究表明：(1)在母体化合物的3和11位引入适合的取代基可使此类化合物抗肿瘤活性明显增强；(2)N3(N11)上引入一个烷基时,随着烷基的体积增大,化合物的抗肿瘤活性减弱；(3)N3(N11)上引入两个烷基时,二乙基衍生物抗肿瘤活性强于二甲基衍生物；(4)二苯并氧杂蒽母体14位有对卤苯基取代时,抗肿瘤活性最好,14位有邻卤苯基取代时,抗肿瘤活性较弱；(5)此类化合物的抗肿瘤活性可能受3、11和14位的取代基共同影响；化合物35、37、38、40、30、31和32对白血病NB4细胞的IC50值分别为0.82、0.96、2.06、2.38、3.08、4.12和4.01μM,均小于阳性药As2O3的5.01μM,具有深入研究的意义。对6,8-二取代二萘并[2,1-b：1’,2’-d]呋喃衍生物抗肿瘤活性研究表明：目标物154、155、159和162对肿瘤细胞的抑制作用较强,其IC50值都小于20μM(母体化合物148的IC50值大于50μM),说明在母体化合物148的6位和8位引入取代基,可增强此类化合物的抗肿瘤活性。对3,11-二取代二萘并[2,1-b：1’,2’-d]呋喃衍生物抗肿瘤活性研究表明：化合物161对肝癌细胞SMMC-7721的IC50值为0.57μM小于阳性对照品As2O3的9.13μM,另外,化合物178对NB4的IC50值也达到了5.07μM,这两个化合物需要进行进一步的抗肿瘤活性研究。可以看出在二萘并[2,1-b：1’,2’-d]呋喃化合物148的3位和11位引入适合的取代基,可明显增强此类化合物的抗肿瘤活性。本论文以抗肿瘤活性的较好的化合物37和38为代表,利用流式细胞法研究了它们对HeLa细胞的抑制机制。研究结果表明：化合物37和38对肿瘤细胞的抑制作用主要是通过诱导细胞凋亡产生的。更多还原

【Abstract】 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.更多还原