大黄素衍生物的合成研究

本文通过甲基化反应和NBS反应,对大黄素的6位进行了化学修饰工作．共合成得到14个大黄素衍生物．并测试了它们对白血病细胞K562和Jurkat的毒性实验。虽然这些衍生物的活性没有明显高于大黄素本身,但对大黄素进行化学修饰仍然是一个有益的研究。     

大黄素10位希夫氏碱衍生物的合成与体外抗肿瘤活性初步研究

目的:合成大黄素10-位希夫氏碱衍生物并研究其抗肿瘤活性。方法:将大黄素与氨衍生物在无水乙醇中以醋酸催化而合成,用核磁共振氢谱、电子轰击质谱法进行结构表征;用四唑盐(MTT)比色法测定其对k562肿瘤细胞增殖抑制率并计算其IC50值。结果:合成了3个大黄素10-位希夫氏碱衍生物,对k562肿瘤细胞的IC50值分别是4.5,3.8,2.0μmol·L-1。结论:大黄素10位希夫氏碱衍生物提高了其母体化合物的抗肿瘤活性并增加了成药性,值得进一步研究。     

大黄素三甲氧基衍生物合成及体外抗肿瘤活性试验

目的:以天然存在的大黄素为原料合成了甲基化衍生物三甲氧基大黄素,并进行体外抗肿瘤活性的研究。方法:利用硫酸二甲酯/丙酮甲基化组合合成目标化合物1,3,8-三甲氧基-6-甲基蒽醌;通过常规方法,对其理化性质进行鉴定。采用HPLC及ESI-MS对其结构进行表征;通过MTT比色法与流式细胞术检测其对K562细胞增殖及细胞周期分布的影响。结果:三甲氧基大黄素为淡黄色粉末,mp:226～227℃,溶于氯仿等有机溶剂。其结构经HPLC及ESI-MS检测得到确证;浓度依赖性地抑制K562细胞的增殖,并使G0/G1期的细胞比例增加。结论:以大黄素为原料,成功合成了其新的衍生物。三甲氧基大黄素具有抑制K562细胞增殖及阻滞细胞周期由G0/G1期向S期移行的抗肿瘤活性。     

大黄素衍生物抗肿瘤活性的定量构效关系

目的 建立大黄素衍生物抗肿瘤活性的构效关系模型.方法 采用量子化学的AM1算法计算了12个大黄素衍生物的分子结构参数,利用逐步回归分析建立构效关系模型.结果 成功建立了大黄素衍生物抗肿瘤活性的构效关系模型.结论 大黄素衍生物抗肿瘤活性与分子体积V、极化率α及C环上净电荷QC相关.     

水溶性大黄素衍生物的合成及抗白血病的初步研究

目的 改善大黄素衍生物的水溶性问题,以期得到一些抗白血病活性较好的大黄素衍生物。方法 以大黄素为原料,经过羟基保护、N-溴代丁二酰亚胺(NBS)参与的溴代反应、与叔胺成盐反应制得目标化合物。结果与讨论 合成了11个未见文献报道的大黄素衍生物,其结构经IR、¹H-NMR谱和元素分析确证。化合物 3h 、3i 和 3j 对白血病细胞 K562 和 Jurkat 细胞株有较好的活性。     

杂环熊果酸衍生物的合成及抗肿瘤活性研究

目的 设计、合成具有抗肿瘤活性的杂环熊果酸衍生物.方法 以天然产物熊果酸为先导化合物,经过氧化和缩合反应得到了一系列含有杂环的熊果酸衍生物,并通过MTT法测试化合物抗肿瘤活性.结果 合成了4个含有杂环的熊果酸衍生物,其结构均通过1H NMR加以确认.初步的生物活性结果表明,这些杂环熊果酸对五种肿瘤细胞均有抑制活性,尤其是喹喔啉熊果酸6对MCF-7、GBC-823和KB肿瘤细胞的抑制活性均强于先导化合物熊果酸;同时,这些杂环熊果酸对正常的乳腺上皮细胞MCF-10A没有毒性.结论 本研究为五环三萜类化合物的构效关系及生物活性研究提供了信息和依据.     

1-吲哚基取代β-咔啉生物碱及其衍生物的合成和初步抗肿瘤活性

目的设计合成eudistomin U及其6位甲氧基/溴取代衍生物和5′位溴取代衍生物并测试其抗肿瘤活性。方法以吲哚-3-甲醛或5-溴-吲哚-3-甲醛和色胺或取代色胺为原料先缩合,再通过Pictet-Spengler反应环合得到四氢-β-咔啉,然后用DDQ脱氢芳构化得到目标化合物。结果合成了eudistomin U及其6位甲氧基/溴取代衍生物和5′位溴取代衍生物,利用核磁共振、质谱、高分辨质谱确认结构。结论合成了海洋生物碱eudistomin U及其一系列衍生物,初步体外抗肿瘤试验结果表明它们均具有一定的抗肿瘤活性。     

大黄素衍生物对口腔底癌细胞活性的构效关系研究

目的探索建立大黄素衍生物抗口腔底癌细胞活性的构效关系模型。方法采用量子化学的AM1半经验算法,计算10个大黄素衍生物分子结构参数,并用逐步回归分析方法,拟定大黄素衍生物抗口腔底癌细胞活性的构效关系模型。结果建立了大黄素衍生物抗口腔底癌细胞活性的构效关系模型。结论大黄素衍生物抗口腔底癌细胞活性与此类化合物分子的疏水性参数、A环上的负电荷及第二条最低空轨道能量有关。     

海藻糖新衍生物的设计、合成及对HIV-1 Tat-TAR结合的抑制活性

目的:设计合成海藻糖新衍生物,研究其对HIV-1 Tat蛋白-TAR RNA结合的抑制活性.方法:以α,α-海藻糖(α,α-trehalose)为原料,经过溴化、乙酰化、叠氮化、催化氢化、缩合及胍基化等6步反应合成目标化合物.在基因水平上探讨其抑制HIV-1 Tat蛋白-TAR RNA结合的活性.结果:合成了一系列海藻糖新衍生物,其抗HIV-1 Tat蛋白-TAR RNA结合活性表明在海藻糖连接精氨酸或连有胍基的侧链后可以增强活性.结论:所设计、合成的带胍基的海藻糖新衍生物具有抑制HIV-1 Tat蛋白-TAR RNA结合的活性.     

氨基噻唑衍生物的合成与药理活性研究

目的:合成氨基噻唑类衍生物并研究其抗流感病毒活性。方法:以氨基噻唑类化合物为母核,合成一系列神经氨酸酶抑制剂,通过在体方法检测其对流感病毒的抑制活性。结果与结论:合成了6个新化合物,其中部分化合物具有一定的抗流感病毒活性。     

新型查尔酮类化合物的合成及其抗肿瘤活性

目的 设计并合成新型查尔酮类化合物, 初步评价其体外抗肿瘤活性。方法 以2,4-二羟基苯乙酮为原料,经酚羟基烷基化、氯甲基化、氮烷基化、 羟醛缩合 4 步反应合成目标化合物。以A-549(人肺腺癌细胞株)、SGC-7901(人胃癌细胞株)、SW-1990(人胰腺癌细胞株)、MCF-7(人乳腺癌细胞株) 4 种肿瘤细胞为测试细胞株, 采用 MTT 法测定目标化合物的抗肿瘤活性。结果与结论 合成了 16 个新型查尔酮类化合物, 其结构经 ¹H-NMR 谱确证。体外抗肿瘤活性数据表明: 合成的目标化合物具有较好的抗肿瘤活性, 可进行更深入的研究。     

Apoptosis-inducing activity of new pyrazole emodin derivatives in human hepatocellular carcinoma HepG2 cells

A series of new pyrazole derivatives from emodin synthesized in our lab have been shown to have much stronger cytotoxicity than emodin against various tumor cell lines. This study was to examine the apoptosis-inducing activity of these new emodin derivatives in human hepatocellular carcinoma HepG2 cell culture for a better understanding of their cytotoxic effects on the cancer cells. Several major events in the induction of cell apoptosis, nuclear chromatin condensation, DNA fragmentation, caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage were detected in the cells after treatment with the compounds at various concentrations. Of the seven emodin derivatives tested at a dose of 10 microM and within a treatment period of 24 h, only compounds 1 and 3 effectively induced all these apoptotic events in the cancer cells. The apoptosis-inducing activity of the compounds showed a positive correlation to their cytotoxic activity, suggesting a close connection between the growth inhibition and apoptosis induction of the cancer cells by these pyrazole emodin derivatives.     

2-（E）-（3-甲氧基-4-环戊氧基苯基亚甲基）环戊酮衍生物的合成及抗肿瘤活性

目的设计并合成一系列2-（E）-（3-甲氧基-4-环戊氧基苯基亚甲基）环戊酮衍生物，并对其体外抗肿瘤活性进行筛选。方法合成目标化合物并用人肝癌细胞（Bel-7402）和人口腔癌细胞（KB）对化合物的体外抗肿瘤活性进行筛选。结果合成了5个目标化合物，其中3个未见文献报道。化合物的结构经IR、^1H NMR、MS和元素分析确证。初筛结果显示化合物5具有较高的活性，对Bel-7402和KB细胞的IC50值分别为1．62gmol·L^-1和8．04gmol·L^-1,但低于对照药5-氟脲嘧啶。结论2-（E）-（3-甲氧基-4-环戊氧基苯基亚甲基）环戊酮Mannich碱衍生物具有一定抗肿瘤活性。     

Synthesis,Tautomeric Structures,and Antitumor Activity of New Perimidines

New series of perimidine derivatives and fused perimidines were derived from the reaction of ketene aminals 1 and 2 with diazotized anilines or hydrazonoyl chlorides. In addition, 8,10‐disubstituted‐[1,2,4]triazolo[4,3‐a]perimidines ( 20a–m ) were prepared through the reaction of perimidine‐2‐thione ( 15 ) with hydrazonoyl chlorides. The structures of the newly synthesized compounds were established on the basis of spectral data and elemental analyses. Some products were investigated for their antitumor activities against the human breast cancer cell line MCF‐7 and the liver carcinoma cell line HEPG‐2, and the results of some derivatives showed promising activity.     

Aloe–emodin modulates PKC isozymes, inhibits proliferation, and induces apoptosis in U-373MG glioma cells

Aloe–emodin (1,8-dihydroy-3-[hydroxymethyl]-anthraquione) purified from Aloe vera leaves has been reported to have antitumor activity. The objectives of our research were to determine how aloe–emodin regulates the cell cycle, cell proliferation and protein kinase C (PKC) during glioma growth and development. To establish the cell cycle effects of aloe–emodin on brain cells [transformed glia cell line (SVG) and human glioma U-373MG cell line (U-373MG)], cells were treated with either dimethylsulfoxide (DMSO; control) or aloe–emodin (40 μM). Results from flow cytometry demonstrated that aloe–emodin delayed the number of cells entering and exiting DNA synthesis (S) phase in both SVG and U-373MG cells indicating that aloe–emodin may inhibit S phase progression. Assessment of cell viability demonstrated that SVG and U-373MG glioma cell were highly sensitive to aloe–emodin. The aloe–emodin-induced decreased proliferation was sustained at 48–96 h. A PKC activity assay was quantified to establish the role of PKC in aloe–emodin's mode of action. Exposure of SVG and U-373MG glioma cells to aloe–emodin suppressed PKC activity and reduced the protein content of most of the PKC isozymes. We determined that cancer growth inhibition by aloe–emodin was due to apoptosis (i.e., programmed cell death). Taken together, these results support the hypothesis that aloe–emodin represents a novel antitumor chemotherapeutic drug.     

Synthesis and cytotoxic studies of hydroximino derivatives of some 16E-arylidenosteroids

Oxime and dioxime derivatives of various 16E-arylidenosteroids in the androstene series have been prepared and evaluated at the National Cancer Institute (NCI), Bethesda (USA) for their antineoplastic activity against various tumor cell lines in order to determine the structural requirements for cytotoxic activity. Aldol condensation of dehydroepiandrosterone (DHA) and DHA acetate with various aldehydes followed by treatment with hydroxylamine hydrochloride resulted in the formation of 16E-arylidenosteroid-oxime system. Oximes 15, 16 and compound 20 with a higher degree of oxidation in ring A have been found active in a 60 cell line antitumor prescreen by virtue of their cytotoxic effect against one or more tumor cell line and were further referred for in vivo hollow fiber bioassay. These compounds showed interesting intraperitoneal and subcutaneous scores in the in vivo hollow fiber bioassay and have been referred to the Biological Evaluation Committee for Cancer Drugs for further detailed in vivo testing.     

Synthesis and Antitumor Activity of Natural Compound Aloe Emodin Derivatives

In this study, we have synthesized novel water soluble derivatives of natural compound aloe emodin 4(a–j) by coupling with various amino acid esters and substituted aromatic amines, in an attempt to improve the anticancer activity and to explore the structure–activity relationships. The structures of the compounds were determined by ¹H NMR and mass spectroscopy. Cell growth inhibition assays revealed that the aloe emodin derivatives 4d, 4f, and 4i effectively decreased the growth of HepG2 (human liver cancer cells) and NCI‐H460 (human lung cancer cells) and some of the derivatives exhibited comparable antitumor activity against HeLa (Human epithelial carcinoma cells) and PC3 (prostate cancer cells) cell lines compared to that of the parent aloe emodin at low micromolar concentrations.