2,6—哌嗪二酮类抗肿瘤药物的研究1—取代苯基—4—（2‘,3’—二乙酰…

本文设计合成了１１个１－取代苯基－４－（２’，３’－二乙酰氧基－５’－甲氧羰基苄基）－２，６－哌嗪二酮类化合物，并经过小鼠白血病细胞Ｐ３８８、小鼠肝癌细胞Ｈｅｐ和人体胃癌细胞ＳＧＣ７９０１的体外实验表明，化合物９ｊ对Ｐ３８８白血病细胞有较强的抑制作用，化合物９ｄ对Ｈｅｐ肝癌细胞有较强的抑制作用，本文还考察了超声波辐射时间对Ｍａｎｎｉｃｈ反应的影响。     

2－［1－环戊烯（1）基］－2－烃基环戊酮Mannich碱的合成及抗癌、抗炎活性研究

本文报道２－［１－环戊烯（１）基］－２－烃基环戊酮Ｍａｎｎｉｃｈ碱类化合物的合成方法，共合成了１２个未见文献报道的新化合物。关键中间体２－［１－环戊烯（１）基］－２－烃基环戊酮是中间体α－位上引入烃基而制备的，然后经Ｍａｎｎｉｃｈ反应制备了目标化合物。对大部分化合物进行了抗癌、抗炎活性筛选。初步结果表明所有化合物对ＥＡＣ和ＨｅｐＡ癌细胞都有较强的杀伤作用。部分化合物对Ｐ３８８，Ｈｅｐ２及Ｈｅｌａ细胞也有很强的抑制作用．某些化合物还显示有效强的抗炎作用，进一步的药理实验正在进行中．     

2－（E）－烷亚甲基环己酮Mannich碱盐酸盐类化合物的合成及抗癌、抗炎活性研究

本文设计、合成了２－（Ｅ）－烷亚甲基环己酮Ｍａｎｎｉｃｈ碱盐酸盐类化合物２４个；其中２２个为未见文献报道的新化合物。初步药理结果显示：大部分化合物对Ｐ３８８和Ｈｅｌａ细胞均有作用，特别是化合物Ⅱ２３，它对两种细胞的ＬＣ５０分别为４．１０１ｍｇ／Ｌ和０．１３５ｍｇ／Ｌ；部分化合物对Ｌ１２１１０和Ｈｅｐ２细胞也有一定的抑制作用；动物体内实验也显示出一定的活性。该类化合物还有效强的抗炎活性，有些化合物的抗炎活性与消炎痛相当。     

双（2，6－哌嗪二酮）类抗肿瘤药物的研究：2，3－二乙酰氧基－1，4－二（3′，5′－二酮－N4′－取代哌嗪甲基）苯的合成

双（２，６－哌嗪二酮）类抗肿瘤药物的研究：２，３－二乙酰氧基－１，４－二（３′，５′－二酮－Ｎ４′－取代哌嗪甲基）苯的合成李全，沈旭，邵华武，谢毓元（中国科学院上海药物研究所２０００３１）１９６９年Ｃｒｅｉｇｈｔｏｎ等人试图用ＥＤＴＡ与甲酰胺反应合成...     

2，2′-二硫代双苯甲酸衍生物的合成及其抗血小板聚集作用

根据ＴＸＡ２／ＰＧＨ２ 受体拮抗剂的结构特征,设计合成了１６ 个２ ,２′二硫代双苯甲酸衍生物,部分目标化合物在体外对ＡＤＰ 诱导的兔血小板聚集均有不同程度的抑制作用,其中化合物（Ｉ３） 活性较强．     

2—（E）—烷亚甲基环已酮Mannich碱盐酸盐类化合物的合成…

本文设计、合成了２－（Ｅ）－烷亚甲基环已酮Ｍａｎｎｉｃｈ碱酸盐类化合物２４个；其中２２个为未见文献报道的新化合物。初步药理结果显示：大部分化合物对Ｐ３８８和Ｈｅｌａ细胞均有作用，特别是化合物Ⅲ２３，它对两种细胞的ＬＣ５０分别为４．１０１ｍｇ／Ｌ和０．１３５ｍｇ／Ｌ；部分化合物对Ｌ１２１０和Ｈｅｐ２细胞也有一定的抑制作用；动物体内实验也显示出一定的活性，该类化合物还有较强的抗炎活性，有些化合物的抗炎     

4－（2′－乙氧羰基乙基）－1，7－庚二酸二乙酯的新合成方法

本文报道４－（２′－乙氧羰基乙基）－１，７－庚二酸二乙酯的新合成方法。关键反应步骤采用三正丁基锡氢通过游离基还原反应脱除叔碳硝基，总收率以硝基甲烷计算为６５．４％。     

2，4－二氨基5－氟－6－取代苄氨基喹唑啉的合成及生物活性

本文报道２，４－二氨基－５－氟－６－取代苄氨基喹唑啉类化合物的合成及抗疟、抗肿瘤和抗菌活性，这类化合物的合成是由５－氟－２，４，６－三氨基喹唑啉（６ａ）与取代苯甲醛缩合成Ｓｃｈｉｆｆ碱，然后经还原、甲酰化、亚硝化或甲基化制得。５－氟－２，４，６－三氨基喹唑啉（６ａ）尚未见文献报道，由５－氟－２，４－二氨基喹唑啉（４）经硝化生成异构体５ａ和５ｂ分离得５ａ后再经还原制得。经对伯氏鼠疟原虫Ｐｌａｓｍｏｄｉｕｍｂｅｒｇｈｅｉ抑制性治疗筛选，有６个化合物Ｉ２，４．５，６和ＩＩ５，６以每日１ｍｇ·ｋｇ－１，给药４天，抑制率为１００％；体外抗肿瘤活性以Ｉ４最强，对Ｌ１２１０白血病细胞的ＩＣ５０为９．８６×１０－４μｇ·ｍｌ－１，优于氨甲蝶呤（ＭＴＸ）；经对１８种常见菌进行体外筛选，发现对肺炎双球菌Ｄｉｐｌｏｃｏｃｃｕｓｐｎｅｕｍｏｎｉａｅ活性较好。     

6，7－二甲氧基－2，4－二羟基喹唑啉合成工艺的改进

以藜芦醛（２）为原料经硝化－氧化得硝基酸４，再按类似物６－甲氧基－７－苄氧基－２，４－二羟基喹唑啉的合成法经酰氯－酰胺化、还原和环合反应合成了标题化合物１。对各步反应的工艺条件和后处理方法进行了改进，使从２至１的总收率达２０．６％。     

制备N－2，6－二氯苯胺的新工艺路线研究

以环己酮为起始原料经２，２，６，６－四氯环己酮制备Ｎ－苯基－２，６－二氯苯胺（双氯灭痛的中间体）的新工艺路线。工艺简单、产品质量好、＂三废＂少，可较大幅度降低成本。     

双(2,6-哌嗪二酮)类抗肿瘤药物的研究:2,3-二乙酰氧基-1,4-二(3′,5′-二酮-N4′-取代哌嗪甲基)苯的合成

Seventeen compounds having the structure of 2,3-diacetoxy-1,4-bis(3′,5′- dioxo-N⁴′-substituted piperazinyl methyl)benzene were designed and synthesized based on chelation hypothesis. Their antitumor activities on P388 cells,Hep cells and SGC 7901 cells in vitro were tested. Preliminary results showed that compound 4e has potent antitumor effect against P388 cells and.Hep cells in vitro.     

Synthesis and evaluation of antitumor activity of novel 2-[<Emphasis Type="Italic">N</Emphasis>-Methyl-<Emphasis Type="Italic">N</Emphasis>-(4-methyl-1,3-benzothiazol-2-yl)aminomethyl]-5,8-diacyloxy-1,4-naphthoquinones

A series of nine new compounds bridged by acyl groups at the 5,8-dihydroxyl group of DHNQ were synthesized and their cytotoxic activity against L1210 and P388 cancer cells was examined. Their antitumor action in mice bearing S-180 cells in the peritoneal cavity was also assessed. Increasing the size of the acyl group (compounds 7–9) up to propyl increased the antitumor activity (T/C value), whereas the cytotoxicity of these compounds was comparable against L1210 (lymphocytic leukemia) and P388 (lymphoid neoplasm) cancer cells. Further increasing in the chain length (compounds 11–15) decreased the potency. Thus, acyl group chains of three carbon atoms is optimal for antitumor activity. The most potent compound of this series was 2-[N-methyl-N-(4-methyl-1,3-benzothiazol-2-yl)aminomethyl]-5,8-dipropylcarbonyloxy-1,4-naphthoquinone (compound 9) with a T/C (%) value of 354.     

In vitro cytotoxicity of S16020-2, a new olivacine derivative

Summary S16020-2 is a new olivacine derivative which has recently shown a marked antitumor activity in various experimental models. This study was undertaken in order to measure the inhibition of the proliferation of various sensitive and resistant tumor cell lines, by S16020-2, and to obtain information concerning its mechanism of action.For a continuous exposure, S16020-2 was as cytotoxic as adriamycin (ADR) (mean IC₅₀ of about 28 nM) and on average, 46 fold more potent than elliptinium acetate (ELP), against a panel of 20 non-multidrug resistant cell lines. With a short exposure (1 hour) followed by a post-incubation of 95 hours in drug-free medium, S16020-2 was 5 and 6 fold more cytotoxic than ADR for human lung A549 and murine melanoma B16 cells, respectively. Furthermore, S16020-2 inhibited more actively the formation of colonies issued from proliferating cells, compared to colonies issued from quiescent A549 cells. Because quiescent cells demonstrated a 3 fold lower level of topoisomerase II (topo II) than proliferating cells, these results suggest that this enzyme could be a potential target for S16020-2. In addition, as demonstrated by flow cytometric studies, S16020-2 intercalated into DNA and induced a cell cycle arrest in G2.Cell lines displaying the multidrug resistance (MDR) phenotype, P388/ADR-1, P388/ADR, P388/VCR-20, KB-A1, DC-3F/AD, S1/tMDR, and Colo320DM, were more sensitive to S16020-2 than to ADR or ELP, as shown by the mean resistance factors, 8, 201, and 23 respectively. In addition, the two cell lines displaying the pure classical MDR phenotype, linked exclusively to the P-glycoprotein (P-gp) overexpression (P388/VCR-20 and S1/tMDR), were as sensitive to S16020-2 as their sensitive parental counterparts, although they were resistant to ADR.S16020-2 is thus one of the most potent olivacine and ellipticine derivative yet characterized. The good cytotoxicity of S16020-2 against cells displaying a P-gp-mediated multidrug resistance, and its antitumor activity in vivo delineate an important chemotherapeutic potential for this drug.     

3-甲基-7-氧-9-氟-10-烃氧基(或芳氧基)-2,3-二氢-7H-吡啶[ 1,2,3-de]苯并恶嗪-6-羧酸及其类似物(英) 的合成和抗菌以及抗肿瘤活性

合成了3－甲基－7－氧－9－氟－10－烃氧基（或芳氧基）－2,3－二氢－7H－吡啶［1,2,3－de］苯并恶嗪－6－羧酸及其类似物,体外抗菌筛选证明10－烃氧基化合物（尤其是氟乙氧基化合物3d）的抗菌作用明显优于10－羟基化合物3a。体外抗肿瘤试验证明有的化合物对LAX和P388细胞株培养具有中等或较低的细胞毒。     

Inhibitory effect of Daesungki-Tang on the invasiveness potential of hepatocellular carcinoma through inhibition of matrix metalloproteinase-2 and -9 activities

Daesungki-Tang (DST), a drug preparation consisting of four herbs, that is, Rhei radix et rhizoma (RR; the roots of Rheum coreanum Nakai, Daehwang in Korean), Aurantiii frutus immaturus (AFI; immature fruits of Poncirus trifolita Rafin., Jisil in Korean), Magnoliae cortex (MC; the stem bark of Magnolia officinalis Rehd. Et Wils., Hubak in Korean), and Mirabilite (MS; Matrii sulfas, Mangcho in Korean), is a traditional Korean herbal medicine that is widely used in the treatment of cancer metastasis, gastrointestinal complaints, vascular disorders, and atherosclerosis-related disorders. In this study, water extracts of DST and each of the four ingredient herbs were prepared. The extracts were tested for cytotoxic activity on human hepatocellular carcinoma cells, Hep3B cells using the XTT assay method. The inhibitory effect of the extracts on the invasion of Hep3B cells was also tested using matrigel precoated transwell chambers. DST effectively inhibited the invasion of Hep3B cells, compared with the control groups in a dose-dependent manner. In addition, a gelatin zymography assay showed that DST decreased the gelatinolytic activity of matrix metalloproteinases-2 (MMP-2; IC50 = 87 microg/ml) and -9 (MMP-9; IC50 = 75 microg/ml) that are secreted from Hep3B cells, respectively. Among the four herbal ingredients of DST, only MC has been shown to significantly inhibit the invasion of Hep3B cells and MMP-2 and -9 activities. From these results, it can be concluded that DST has some potential for use as an antitumor agent.     

Synthesis and anticancer activities of 4-oxobenzopyrano[2,3-d]pyrimidines

Several 2-aryl-4-oxoxbenzopyrano[2,3-d]pyrimidines have previously been shown to exhibit in vivo antitumor activity in mice with P388 lymphocytic leukemia. In the present study, a series of novel substituted benzopyrano[2,3-d]pyrimidines have been prepared and tested for cytotoxic activity against a panel of cancer cell lines including the P388 lymphocytic leukemia cell line. The unsubstituted parent compound, some methoxylated derivatives and a cyclohexyl derivative all exhibited potent cytotoxic activity (IC50 values 0.3-0.64 microM). A number of derivatives, including the unsubstituted parent pyrimidine, were shown to cause a significant perturbation in cell cycle kinetics with an observed 2- to 3-fold increase in cells in the G2/M phase of the cell cycle. Furthermore, a polymethoxylated derivative, 2-(3,4,5-trimethoxyphenyl)-9-methoxy-4-oxo-2,3-dihydrobenzopyrano[ 2,3-d]pyrimidine 13, was shown to be selectively active against a number of human ovarian cell lines.     

Synthesis of 9-O-substituted derivatives of 9-hydroxy-5, 6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylic acid (2-(dimethylamino)ethyl)amide and their 10- and 11-methyl analogues with improved antitumor activity.

Analogues of the antitumor drug S 16020-2 modified at the 9, 10, or 11 position were synthesized and evaluated in vitro and in vivo on the P388 leukemia and B16 melanoma models. Starting from 9-methoxy-5, 11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylic acid ethyl ester, the 11-CH3 analogue of 9-hydroxy-5,6-dimethyl-6H-pyrido[4, 3-b]carbazole-1-carboxylic (2-(dimethylamino)ethyl)amide (1), compound 4, was synthesized using a four-step sequence, whereas its 10-CH3 analogue 5 was prepared using a two-step pathway, starting from compound 1. Finally starting from the 9-OH compounds 1, 4, and 5, a series of variously 9-O-substituted derivatives were synthesized. In these series, the most active compounds resulted from esterification of the 9-OH group with various aliphatic diacids, which led to 9-O-CO-( )-COOH derivatives of 1, 4, and 5. For these compounds, the number of long-term surviving mice obtained at the optimal dose were 60-100% in the ip/iv P388 leukemia and 10-35% in the ip/ip B16 melanoma, corresponding to an improved therapeutic index with respect to 1 and 4. This high antitumor activity, with curative examples in both models, was not due to a higher cytotoxicity since these compounds were equally or slightly less potent in vitro than 1 and 4. The most active compounds were thus selected for further in vivo evaluation.     

Reversal of resistance to doxorubicin with cepharanthine in murine P388 leukemia cells

Cytotoxic effect in vitro and antitumor effect in vivo of doxorubicin (DOX) combined with cepharanthine were investigated on DOX-resistant murine P388 leukemia (P388/R) cells. Cepharanthine was minimally cytotoxic in the cell line, but reversed DOX-resistance in a dose-related manner in P388/R cells. The administration of cepharanthine to mice bearing the P388 leukemia enhanced the antitumor activity of DOX. These results indicate that cepharanthine is an effective agent to reverse DOX-resistant cells.     

国产米托蒽醌对小鼠实验性肿瘤抗瘤活性研究

实验证明国产米托蒽醌无论静脉、腹腔、皮下或灌胃给药,对小鼠S_(180)均有强的抑瘤作用,化疗指数为6.05。本品对小鼠P_(388)白血病、L_(1210)白血病、肝癌腹水型及lewis肺癌的抗瘤活性高于或相当于阿霉素。     

Compounds with potential antitumor activity. VI--2-Alkyl-3-[2-(1,3,4-thiadiazolyl)]-4-thiazolidinones

The antitumor activity of a series of 2-alkyl-3-[2-(1,3,4-thiadiazolyl)]-4-thiazolidinones was tested against the leukemic P 388 tumor system in mice. Only compounds (V-VII) showed significant activity.