鬼臼毒素衍生物的合成及其体外抗肿瘤活性

目的 获得更高活性且具有抗多药耐药活性的抗肿瘤新化合物。方法 将4β-氨基-4-脱氧鬼臼毒素与醇类化合物以丁二酸为桥连接合成了7个鬼臼毒素衍生物,其结构经1H-NMR、TOF-MS证实。用K562和K562/AO2细胞经MTT法筛选了这些衍生物的体外抗肿瘤活性。结果 7个化合物均为新化合物,其中5b、5d的抗肿瘤活性显著高于VP-16, 并且5b、5c、5d、5e的抗多药耐药活性显著高于VP-16。结论 这些鬼臼毒素衍生物可提高抗肿瘤活性。     

司他夫定衍生物的合成及抗肿瘤活性评价

目的设计合成一系列司他夫定类衍生物,并评价其抗肿瘤活性。方法以司他夫定为原料,经磺酸酯化后与叠氮化钠反应生成5'-叠氮基司他夫定,再通过Huisgen 1,3-偶极环加成反应得到目标化合物。采用MTT法分别以人肝癌细胞(BEL-7402)、人胃癌细胞(BGC-823)、肺癌细胞(A549)为测试细胞株对目标化合物进行体外抗肿瘤活性评价。结果与结论合成了14个5'-脱氧司他夫定衍生物,目标化合物的结构经核磁共振氢谱和碳谱确证。其中化合物4k对人肝癌细胞(BEL-7402)、人胃癌细胞(BGC-823)、肺癌细胞(A549)具有中等的抑制作用。     

13-酰胺基取代苦参碱衍生物的合成及抗肿瘤活性研究

目的 合成13-酰胺基取代苦参碱衍生物及研究该类化合物的体外抗肿瘤活性。方法 以槐果碱为原料,通过迈克尔加成（Michael addition）,叠氮还原酰化反应,制得系列13-位酰胺取代的衍生物,所有化合物结构均经¹H NMR等谱确证;选取人肝癌细胞（BEL-7404）和小鼠黑色素瘤细胞（K111）对所合成的目标化合物进行体外抗肿瘤药理活性筛选。结果 设计合成了9个新化合物,大多数化合物对两株肿瘤细胞都具有较强的抑制活性。结论 化合物4b和4e对人肝癌细胞（BEL-7404）有较强的抑制活性。     

硫代秋水仙碱衍生物的合成和抗肿瘤活性

目的寻找高效低毒的秋水仙碱抗肿瘤衍生物。方法秋水仙碱首先被转化为硫代秋水仙碱，然后硫代秋水仙碱通过水解得到7-(N-脱乙酰基硫代秋水仙碱)，最后经胺的酰化得到目标化合物。用¹H NMR，IR，MS和HR-MS确证了这些衍生物的结构，MTT法评价了目标衍生物的细胞毒性；用对小鼠肝癌H₂₂和宫颈癌U₁₄的抑制率评价了衍生物的体内抗肿瘤活性。结果合成了12个硫代秋水仙碱新衍生物。结论尽管一些硫代秋水仙碱衍生物的体外细胞毒性强于秋水仙碱，然而小鼠体内抑瘤活性却较低。     

新型槲皮素衍生物的合成及其抗肿瘤活性研究

目的 设计并合成以槲皮素为母核,研究3′-位羟基引入芳香丙烯基槲皮素衍生物的体外抗肿瘤活性。方法 以槲皮素为原料,用不同取代的芳香丙烯酸与其3′-位羟基缩合成酯,得目标槲皮素衍生物,并通过核磁共振波谱仪(¹H-NMR)进行结构表征,同时用噻唑蓝比色法(MTT法)测试目标化合物对不同肿瘤细胞的抗肿瘤活性。结果 通过抗肿瘤活性测试显示,所合成的目标化合物对人结肠癌细胞和乳腺癌细胞表现出了较好的抗肿瘤活性,均达到了微摩尔级,其中化合物5C₁和5C₆对乳腺癌肿瘤细胞的细胞毒达到了10微摩尔级,半抑制浓度(IC₅₀)分别为10.59 μmol/L和10.31 μmol/L。结论 该系列槲皮素衍生物的合成为后续槲皮素衍生物的合成研究和获得具有潜在抗肿瘤活性的先导化合物奠定了基础。     

Synthesis and antitumor activity of 3-arylisoquinoline derivatives

In order to study the structure-activity relationship of 7,8-dimethoxy-2-methyl-3-(4,5-methylen-edioxy-2-vinylphenyl)isoquinoline-1 (2H)-one (2), which has exhibited significant antitumor activity, chemical modifications of2 were performed to yield the corresponding products (3–7). Further systematic uses of an efficient procedure for the synthesis of 3-arylisoquinoline derivatives produced the substituted compounds (9a−9g), which were tested forin vitro antitumor activity against five different human cancer cell lines.     

Synthesis and antitumor activity of 1,3-benzodioxole derivatives

A series of 1,3-benzodioxoles (5-19) was synthesized and evaluated for their in vitro antitumor activity against human tumor cell lines. Some derivatives exhibited tumor growth inhibition activity. In particular, 6-(4-aminobenzoyl)-1,3-benzodioxole-5-acetic acid methyl ester 8, the most active compound of the series, possesses a significant growth inhibitory activity on 52 cell lines at concentrations ranging from 10(-7) to 10(-5) M.     

In-vitro antitumor activity evaluation of hyperforin derivatives

The derivatives of hyperforin, namely hyperforin acetate (2), 17,18,22,23,27,28,32,33-octahydrohyperforin acetate (3), and N,N-dicyclohexylamine salt of hyperforin (4), have been investigated for their antitumor properties. In-vitro studies demonstrated that 2 and 4 were active against HeLa (human cervical cancer), A375 (human malignant melanoma), HepG2 (human hepatocellular carcinoma), MCF-7 (human breast cancer), A549 (human nonsmall cell lung cancer), K562 (human chronic myeloid leukemia), and K562/ADR (human adriamycin-resistant K562) cell lines with IC₅₀ values in the range of 3.2–64.1 μM. The energy differences between highest occupied molecular orbital and lowest unoccupied molecular orbital of 2–4 were calculated to be 0.39778, 0.43106, and 0.30900 a.u., respectively, using the Gaussian 03 software package and ab initio method with the HF/6-311 G* basis set. The result indicated that the biological activity of 4 might be the strongest and that of 3 might be the weakest, which was in accordance with their corresponding antiproliferative effects against the tested tumor cell lines. Compound 4 caused cell cycle arrest at G2/M phase in flow cytometry experiment and induced apoptosis by 4′,6-diamidino-2-phenylindole staining and Annexin V-FITC/PI (propidium iodide) double-labeled staining in HepG2 cells. The results indicated a potential for N,N-dicyclohexylamine salt of hyperforin as a new antitumor drug.     

多取代三氮唑类化合物的合成及其抗肿瘤活性研究

目的设计合成一系列4-胺甲酰-1,5-双芳基-1,2,3-三氮唑类化合物,并评价其抗肿瘤活性。方法以叠氮化钠为原料,经亲核取代反应制成有机叠氮化物后与丙炔酸甲酯通过Huisgen 1,3-偶极环加成反应得到5-碘代-1,2,3-三氮唑,再与单质硫和苄溴类化合物经3步连续反应"一锅法"得到1-对甲氧基苄基-4-甲氧甲酰-5-苄基硫醚-1,2,3-三氮唑,对三氮唑环上的4-甲氧甲酰基进行胺解反应得到目标化合物。采用MTT法测定目标化合物对人乳腺癌细胞(MCF-7)、肝癌细胞(Hep G2)、肺癌细胞(A549)和宫颈癌细胞(He La)的抑制活性。结果与结论合成了15个未见报道的4-胺甲酰-1,5-双芳基-1,2,3-三氮唑类化合物,其结构经1H-NMR、13C-NMR及HR-MS谱确证。其中,化合物7a对Hep G2、A549和He La细胞均表现出中等程度的抑制活性(IC50值分别为23.00、33.88、26.66μmol·L-1),有进一步研究的价值。     

脱氧氟尿苷针剂对小鼠移植性肿瘤的抑制作用

目的 观察脱氧氟尿苷DFUR针剂对动物移植性肿瘤的实验治疗作用。方法 选用肉瘤S180、肝癌HepS、白血病L615和艾氏腹水癌ECA等四株小鼠移植性肿瘤,观察注射途径下脱氧氟尿苷DFUR的抗肿瘤作用。结果 腹腔、静脉或口服给药,DFUR对S180的抑瘤率均大于80％。腹腔给药对HepS的抑瘤率为78％,对L615和ECA的生命延长率为515％和202％。腹腔给药对S180的化疗指数分别为DFUR2．8,FU1．3,FT2071．4和FUDR1．5。结论 无论是静脉、腹腔或口服给药,脱氧氟尿苷DFUR对多种小鼠肿瘤均有明显的抑制作用。与FU,FT207和FUDR相比,DFUR可在较低的毒性下显示更好的抗肿瘤作用。     

薯蓣皂苷元衍生物的抗肿瘤活性研究

目的研究薯蓣皂苷元衍生物在体外的抗肿瘤活性。方法采用MTT法对人恶性黑色素瘤细胞A375、人肺腺癌细胞A549、人肝癌细胞HepG-2及人慢性髓原白血病细胞株K562进行体外抗肿瘤活性试验。结果薯蓣皂苷元衍生物对4个肿瘤细胞株A375、A549、K562、HepG-2具有不同程度的抗肿瘤活性。结论绝大部分薯蓣皂苷元衍生物对4个肿瘤细胞株有较好的抗肿瘤活性,IC50值都低于30μmol.L-1。化合物22对细胞株A375的IC50=4.48μmol.L-1,化合物9、10对细胞株K562的IC50分别为2.51、2.38μmol.L-1;显示其抗肿瘤活性与对照化合物1-(3β-薯蓣皂苷元)-3-苄基咪唑溴盐相当。     

In-vitro antitumor activity evaluation of hyperforin derivatives

The derivatives of hyperforin, namely hyperforin acetate (2), 17,18,22,23,27,28,32,33-octahydrohyperforin acetate (3), and N,N-dicyclohexylamine salt of hyperforin (4), have been investigated for their antitumor properties. In-vitro studies demonstrated that 2 and 4 were active against HeLa (human cervical cancer), A375 (human malignant melanoma), HepG2 (human hepatocellular carcinoma), MCF-7 (human breast cancer), A549 (human nonsmall cell lung cancer), K562 (human chronic myeloid leukemia), and K562/ADR (human adriamycin-resistant K562) cell lines with IC(50) values in the range of 3.2-64.1 μM. The energy differences between highest occupied molecular orbital and lowest unoccupied molecular orbital of 2-4 were calculated to be 0.39778, 0.43106, and 0.30900 a.u., respectively, using the Gaussian 03 software package and ab initio method with the HF/6-311 G* basis set. The result indicated that the biological activity of 4 might be the strongest and that of 3 might be the weakest, which was in accordance with their corresponding antiproliferative effects against the tested tumor cell lines. Compound 4 caused cell cycle arrest at G2/M phase in flow cytometry experiment and induced apoptosis by 4',6-diamidino-2-phenylindole staining and Annexin V-FITC/PI (propidium iodide) double-labeled staining in HepG2 cells. The results indicated a potential for N,N-dicyclohexylamine salt of hyperforin as a new antitumor drug.     

脱氧氟尿苷针剂对小鼠移植性肿瘤的抑制作E用

目的观察脱氧氟尿苷DFUR针剂对动物移植性肿瘤的实验治疗作用.方法选用肉瘤S180、肝癌HepS、白血病L615和艾氏腹水癌ECA等四株小鼠移植性肿瘤,观察注射途径下脱氧氟尿苷DFUR的抗肿瘤作用.结果腹腔、静脉或口服给药,DFUR对S180的抑瘤率均大于80%.腹腔给药对HepS的抑瘤率为78%,对L615和ECA的生命延长率为515%和202%.腹腔给药对S180的化疗指数分别为DFUR2.8,FU1.3,FT207 1.4和FUDR1.5.结论无论是静脉、腹腔或口服给药,脱氧氟尿苷DFUR对多种小鼠肿瘤均有明显的抑制作用.与FU,FT207和FUDR相比,DFUR可在较低的毒性下显示更好的抗肿瘤作用.     

In vitro andin vivo circumvention of multidrug resistance by Servier 9788, a novel triazinoaminopiperidine derivative

Summary S 9788 is a novel triazinoaminopiperidine derivative which does not belong to any of the classes of compounds known to reverse multidrug resistance (MDR). S 9788 was far more potent than verapamil (VRP) in reversing resistance to adriamycin (ADR) in the ADR-selected murine leukaemia cell lines P388/ADR-1 and P388/ADR-10, and the human chronic myelogenous leukaemia K562/R. Fold reversion with S 9788 (5M was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5M). S 9788 was also a more potent reversant of ADR resistance in the intrinsically resistant human colon adenocarcinoma COLO 320DM (2.3 fold), and of vincristine (VCR) resistance in the human MDR1 gene-transfected squamous lung carcinoma line S1/tMDR1 (5.6 fold). The activity of S 9788 depended on both the MDR cell line and the cytotoxic agent. S 9788 (50–100 mg/kg/d) administered IP once a day on days 1–4 resulted in a dose-dependent increase in the chemotherapeutic effect of VCR (0.25 mg/kg/d) in P388/VCR-bearing mice and ADR (4 mg/kg/d) in P388/ADR-bearing mice. Increases in antitumor activity were (% T/C) of +20–34% in the P388/ADR model and +50–78% in the P388/VCR model with respect to cytotoxic agent treatment alone. S 9788 appeared to be devoid of toxicity at its effective doses. The mechanism of action of S 9788 is unknown but S 9788 (0.5–10M) induced a dose-dependent increase in ADR accumulation in KB-Al cells and compared to verapamil its effect was twice as active and approximately seven times more potent. We conclude that S 9788 is a novel agent capable of reversing MDRin vitro andin vivo, and whose pharmacological profile warrants its selection as a candidate drug for eventual assessment in the clinic.     

Synthesis and antitumor activity of quinonoid derivatives of cannabinoids

Three cannabis constituents, cannabidiol (1), Delta(8)-tetrahydrocannabinol (3), and cannabinol (5), were oxidized to their respective para-quinones 2, 4, and 6. In the 1960s, the oxidized product 4 had been assigned a para-quinone structure, which was later modified to an ortho-quinone. To distinguish between the two possible quinone structures, a detailed NMR investigation was undertaken. The original para-quinone structure was confirmed. X-ray crystallography elucidated the structures of the crystalline 2 and 6. All three compounds displayed antiproliferative activity in several human cancer cell lines in vitro, and quinone 2 significantly reduced cancer growth of HT-29 cancer in nude mice.