2-(E)-(3-甲氧基-4-羟基苯亚甲基)-5-(N-取代胺甲基)环戊酮的合成及抗炎活性研究

２（Ｅ）（３甲氧基４羟基苯亚甲基）５（Ｎ取代胺甲基）环戊酮的合成及抗炎活性研究董金华徐莉英秦华李莉许丁元计志忠（沈阳药科大学，沈阳１１００１５）目标化合物设计α亚甲基γ丁内酯和α亚甲基环酮有多种生理活性［１～３］，研究表明它...     

N-〔3-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-2-羟基-丙基〕-氨基乙酸及其衍生物的合成和抗真菌活性

设计合成了Ｎ〔３（１Ｈ１，２，４三唑１基）２（２，４二氟苯基）２羟基丙基〕氨基乙酸及其９个衍生物，均为未见文献报道的新化合物，初步药理试验表明：部分化合物对浅部真菌有一定的活性，除卡氏枝孢霉菌外，对其它深部真菌活性较弱，其中化合物（５ｅ），（５ｈ）对某些真菌的体外活性较强，明显优于氟康唑，但稍弱于酮康唑     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代-2-丙醇的合成及抗真菌活性研究

１（１Ｈ１，２，４三唑１基）２（２，４二氟苯基）３取代２丙醇的合成及抗真菌活性研究张大志周廷森吴义杰刘超美麻铭川冯向庭（第二军医大学药学院，上海２００４３３）氮唑类化合物是目前抗真菌药物研究最为活跃的领域之一。该类化合物可分...     

S-9-(2,3-二羟丙基)腺嘌呤类似物的合成及其对S-腺苷-L-高半胱氨酸水解酶的抑制活性

为了寻找高效、低毒的抗病毒剂，本文通过用腺嘌呤及嘧啶碱基与３氯２甲基丙烯缩合合成６个ＤＨＰＡ类似物的中间体５ａ，５ｂ，６～８ａ和８ｂ。应用ＯｓＯ４催化，在Ｎ甲基吗琳Ｎ氧化物氧化下对烯键进行邻位双羟化，合成了５个ＤＨＰＡ类似物１～４ａ，ｂ。对化合物５ａ，５ｂ，６～８ａ，８ｂ的１ＨＮＭＲ数据进行了初步总结。对４个ＤＨＰＡ类似物测定了它们对Ｓ腺苷Ｌ高半胱氨酸水解酶（ＳＡＨ）的抑制活性，其中化合物１的ＩＣ５０为１１ｍｍｏｌ·Ｌ－１，其余化合物均无抑制活性。     

3-异丙基、3-正戊基环戊二酮-1,2 Mannich碱衍生物的合成及抗癌活性

以３异丙基、３正戊基环戊二酮１，２为母体化合物，设计合成了９个未见文献报道的Ｍａｎｎｉｃｈ碱衍生物，并在体外进行了抗癌活性评价。初步药理活性筛选结果表明，３正戊基环戊二酮１，２Ｍａｎｎｉｃｈ碱衍生物的抗癌活性较强，３异丙基环戊二酮１，２Ｍａｎｎｉｃｈ碱衍生物的活性相对较弱，多数化合物的抗癌活性优于阳性对照药５Ｆｕ．     

7-取代-1-乙基(2-氟乙基)-6,8-二氟-1,4-二氢-4-氧喹啉-3-羧酸的合成及抗菌活性

７取代１乙基（２氟乙基）６，８二氟１，４二氢４氧喹啉３羧酸的合成及抗菌活性鄢立刚徐炳祥马振瀛朱艳静杨倩华（沈阳市沈阳军区后勤部军事医学研究所，沈阳１１００３１；上海市第二军医大学药学院中西药研究室，上海２００４...     

Synthesis of 2-(Alkylthio)-1,2,4-triazolo[1,5-a]pyrimidines and 3-(Alkythio)-1,2,4-triazolo[3,4-a]pyrimidines and Their Vasodilator Activity

本文作者合成了新的５，７二甲基１，２，４三唑并［１，５ａ］嘧啶２苄硫醚类（Ｂ系列）５，７二甲基１，２，４三唑并［３，４ａ］嘧啶２苄硫醚类化合物（Ｄ系列），并测定了这两类化合物在体外对８５７ｍｍｏｌ·Ｌ１Ｋ＋和１０４ｍｍｏｌ·Ｌ１ＮＥ（ｎｏｒｅｐｉｎｅｐｈｒｉｎｅ）引起的血管条收缩的抑制作用。测定结果表明，Ｂ系列化合物的活性均高于Ｄ系列化合物，在苯环的对位有体积较大的疏水性基团有助于生物活性的提高。５，７二甲基１，２，４三唑并［１，５ａ］嘧啶２对溴苄硫醚表现出最好的扩张血管活性，在浓度为１０５ｍｏｌ·Ｌ１和１０４ｍｏｌ·Ｌ１时，对１０４ｍｍｏｌ·Ｌ１ＮＥ引起的离体血管条痉挛的抑制率均为１００％；对８５７ｍｍｏｌ·Ｌ１Ｋ＋引起的离体血管条痉挛的抑制率分别为４７％和１００％。     

6-［4-(取代哌嗪基)苯基］-4，5-二氢-3(2H)-哒嗪酮类化合物的合成及抑制血小板聚集作用

根据哒嗪酮类化合物的构效关系和作用机制,以ＣＣＩ１７８１０ 为先导化合物,设计合成了１８ 个６［４（ 取代哌嗪基） 苯基］４,５二氢３（２ Ｈ）哒嗪酮类化合物．初步的体外药理试验表明：大部分目标化合物都有不同程度的抑制ＡＤＰ诱导的新西兰大白兔血小板聚集的作用,其中化合物（５）的活性最强,比先导化合物强５ 倍,化合物（６）,（７） ,（１２） ,（１３） ,（１６） 的活性也比ＣＣＩ１７８１０ 强,并初步探讨了它们的构效关系．     

7β-N~2-芳基三嗪酰胺基苯乙酰胺基-3-亚甲基杂环头孢烯酸衍生物的合成及其抗菌活性

设计合成了１０个７βＮ２芳基三嗪酰胺基苯乙酰胺基３亚甲基杂环头孢烯酸衍生物及其二钠盐,均为未见文献报道的新化合物,其结构经元素分析数据及光谱分析证实．体外抑菌试验结果表明：化合物（Ⅱ１）,（Ⅱ２）和（Ⅱ３）活性较强,对所选用的１９种菌株均有一定的活性,多数化合物的ＭＩＣ值为８ｍｇ／Ｌ,具有一定的广谱抗菌特征     

若干抗真菌甾体生物碱类似物的合成

为寻找新型抗真菌药物，从易得原料３β乙酰氧基５，１６孕甾二烯２０酮（６）经１０或１１步反应合成了７个抗真菌甾体生物碱类似物，其中１９个为新化合物，化合物３ａ～ｃ和５体外试验抗真菌活性与氟康唑等同或更强。     

Growth inhibition, G1-arrest, and apoptosis in MCF-7 human breast cancer cells by novel highly lipophilic 5-fluorouracil derivatives

In this study we evaluate the antitumour activity, the cell cycle arrest and apoptotic properties of novel lipophilic benzene-fused seven-membered 5-fluorouracil (5-FU) analogs in comparison to 5-FU on MCF-7 human breast cancer cells. The lipophilicities of ESB-786B, ESB-252A and ESB-928A were predicted by using the CDR option of the PALLAS 2.0 program. Cytotoxic assays were evaluated in MCF-7 cells treated with the sulforhodamine B colorimetric method. Cell cycle perturbations were studied by flow cytometry. Apoptosis was determined by both DNA fragmentation and annexin V-FITC and propidium iodide staining. The novel derivatives were more lipophilic than 5-FU and induced a marked growth inhibition, in a dose-dependent manner. After treatment with IC(50) value (ranged from 2.5 to 22 microM) for each compound, light microscopy observation showed modifications in the morphology of MCF-7 cells. In addition, the 5-FU analogs arrest cells in the G(0)/G(1) phase of the cell cycle whereas 5-FU induced arrest in S-phase. Moreover, induction of apoptosis was demonstrated by the annexin-V-based assay and confirmed using DNA fragmentation analysis on MCF-7 cells, a cell line in which the induction of DNA laddering is very difficult. The novel benzannelated seven-membered 5-FU analogs can be considered as specific apoptotic inducers. These experimental findings provide support for the use of these novel compounds as new weapons in the fight against breast cancer.     

7-Bromo-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I), a new tranquillizing agent: metabolism in rats.

1. After intraperitoneal injection of rats with the new benzodiazepine (compound I), four metabolites (compounds II, III, IV and V) were found in the urine. 2. Compound II was identified as 7-bromo-5-(2'-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one by comparison of g.l.c. and mass spectral properties of the metabolite and synthetic compound. 3. Mass spectra of compound III and its acid hydrolysis products indicate that compound III contains a hydroxyl group in the C(5)-phenyl ring. 4. Compounds IV and V were identified by mass spectrometry as products of simultaneous aromatic hydroxylation and methoxylation of the diazepine I. 5. The major urinary excretion products are compounds III, IV and V. Only very small amounts of compounds I and II were detected.     

Oral uracil-tegafur: an alternative to intravenous 5-fluorouracil?

The fluoropyrimidines have been used in the treatment of a number of tumour types over the past 40 years. Particular attention has focused on the use of 5-fluorouracil (5-FU) in colorectal cancer for which, until recently, there has been a lack of other effective chemotherapy. In an attempt to optimise the efficacy of fluoropyrimidines, a number of approaches have been used. These include alternative methods of iv. scheduling, the use of co-factors and the development of oral compounds. The aim of oral agents is to satisfy patient preference while maintaining the efficacy of sustained drug exposure seen with prolonged or continuous infusions of iv. 5-FU. One such oral compound is uracil-tegafur (UFT), which combines tegafur (ftorafur, a 5-FU prodrug) and uracil in a 1:4 molar ratio. UFT first entered Phase I trials in Japan over 20 years ago but has only recently received significant exposure in Phase II and III trials. Results from a number of Phase III studies in Europe and in the US are now becoming available. With UFT recently approved for colorectal cancer in many European countries, although not in the US, it is timely to review the current situation and future prospects for this agent.     

Synthesis and anticancer activities of new 3-allylthio-6-(mono or disubstituted)aminopyridazines

A new series of 3-allylthio-6-(mono or disubstituted) aminopyridazines was synthesized by reacting 3-allylthio-6-chloropyridazine with several amines to develop new anticancer agents. These new compounds showed antiproliferative activities against lung cancer (A549), hepatoblastoma (Hep3b), prostate cancer (PC3), colon cancer (SW480) and cervical cancer (HeLa) cells in MTT assays, and could be promising candidates for chemotherapy of carcinomas. Compound 5 (3-allylthio-6-homopiperidinylaminopyridazine) showed higher potencies than 5-FU for inhibiting the growth of these cell lines. This suggests the potential anticancer activity of compound 5.     

Synthesis of some (E)-6-[2-(furan-2-yl)ethenyl]-1,2,4-triazin-5-ones and their biological evaluation as antitumor agents

The synthesis of some new (E)-6-[2-(furan-2-yl)ethenyl]-1,2,4-triazin-5-ones directly linked to either pyrazole, pyrazoline, pyrazolidine counterparts, or to substituted thio and hydrazono functionalities is described. Six of the newly synthesized compounds were selected by the National Cancer Institute (NCI) to be evaluated for their in vitro antitumor activity according to the protocol of the NCI in vitro disease-oriented human cells screening panel assay. The results revealed that the pyrazole derivative 5c was found to be the most active member in this screen as evidenced by its ability to exert potential growth inhibitory activity against most of the tested subpanel tumor cell lines with selective influence on leukemia subpanel tumor cell lines (GI₅₀ values 2.01–3.03 μM). Moreover, a comparative study for log GI₅₀ values of both compound 5c and 5-fluorouracil (5-FU) revealed that compound 5c showed higher potency than 5-FU against most of the tested subpanel tumor cell lines. Thus compound 5c could be considered as a suitable lead towards the design of broad spectrum antitumor active agents targeting various human tumor cell lines.     

Modulation of 5-fluorouracil cytotoxicity through thymidylate synthase and NF-kappaB down-regulation and its application on the radiolabelled iododeoxyuridine therapy on human hepatoma cell

The inhibition of thymidylate synthase (TS) by 5-fluorouracil (5-FU) was known to increase the incorporation of radiolabelled iododeoxyuridine (IdUrd) into DNA. The relatively non-toxic compounds such as thiol-containing antioxidant pyrrolidinodithiocarbamte (PDTC) or aromatic fatty acid phenylbutyrate (PB) had been reported to enhance the cytotoxic efficacy of 5-FU. We designed a novel strategy through triplet combination of PB, PDTC and 5-FU to increase the radiolabelled IdUrd uptake and investigated the underlying mechanisms. The growth inhibition and [(125)I]IdUrd-DNA incorporation by PB, PDTC, 5-FU in different combinations were tested on parent or p21(Waf1) transfected Hep3B cells. The combination of PB and PDTC was more effective in enhancing 5-FU cytotoxicity than either drug alone. The combination of PB/PDTC and 5-FU blocked cells in S-phase and resulted in 8.5-fold increase of radiolabelled IdUrd-DNA incorporation. The transfection of p21(Waf1) did not change the general pattern of enhancement. Intriguingly, the combination of PB and PDTC effectively down-regulated NF-kappaB and TS and prevented their up-regulation from 5-FU treatment than either drug alone through a p21(Waf1)-independent mechanism. Based on this strategy, the 3-drug combination offered potential for improved radiolabelled IdUrd molecular radiotherapy for hepatoma treatment.     

Emerging drugs in colorectal cancer

A raft of novel agents with different modes of action is finally challenging the position of 5-fluorouracil (5-FU) as the gold standard treatment for colorectal cancer. Oral fluoropyrimidines, topoisomerase I inhibitors and new generation platinum compounds are all currently being investigated. There is also increasing interest in the development and use of biological therapies, which may allow treatments to become tailored to individual patients and cause less toxicity than conventional cytotoxics. It is hoped that with the development of these new drugs, the response rates and survival for patients with colorectal cancer will improve from the poor prognosis that many face at present.     

Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil against adenocarcinoma 755 in mice. Increased therapeutic index and correlation with increased plasma 5-fluorouracil levels

A marked inhibition of the growth of solid tumor adenocarcinoma 755 was achieved by the combination of 5-fluorouracil (5-FU) with bromovinyldeoxyuridine (BVDU). The therapeutic index (LD50/ED50) for the combination of BVDU plus 5-FU was 8.1 and 3.9 upon intraperitoneal (i.p.) or oral (p.o.) administration, respectively. The therapeutic index of i.p. 5-FU given alone was 2.3, whereas for p.o. 5-FU given alone no therapeutic index could be established because of insufficient activity of the compound. Thus, the therapeutic index of 5-FU increased significantly when combined with BVDU. Pharmacokinetic studies revealed that upon i.p. or p.o. 5-FU administration plasma 5-FU levels rapidly declined, but that, in the combination with BVDU, the plasma clearance of 5-FU, especially following p.o. administration, was slowed down considerably. Antitumor activity of 5-FU correlated with AUC (area under the concentration x time curve), within the plasma 5-FU concentration range from 0.02 to 0.4 microgram/ml.     

Emerging drugs in colorectal cancer

A raft of novel agents with different modes of action is finally challenging the position of 5-fluorouracil (5-FU) as the gold standard treatment for colorectal cancer. Oral fluoropyrimidines, topoisomerase I inhibitors and new generation platinum compounds are all currently being investigated. There is also increasing interest in the development and use of biological therapies, which may allow treatments to become tailored to individual patients and cause less toxicity than conventional cytotoxics. It is hoped that with the development of these new drugs, the response rates and survival for patients with colorectal cancer will improve from the poor prognosis that many face at present.