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二氢乳清酸脱氢酶靶向抗疟药研究进展 被引量:1
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作者 赵彩亮 兰晶 +1 位作者 贝祝春 杨恒林 《生物技术通讯》 CAS 2013年第1期124-129,共6页
疟疾是全球危害最严重的传染性疾病之一,尤其是在非洲,发病率与死亡率仍居高不下。抗药性的出现和发展使大多数现有抗疟药在临床上失去了效用,研究和开发新型抗疟药已成为当前疟疾防治研究的迫切需求。随着恶性疟原虫基因组测序的完成... 疟疾是全球危害最严重的传染性疾病之一,尤其是在非洲,发病率与死亡率仍居高不下。抗药性的出现和发展使大多数现有抗疟药在临床上失去了效用,研究和开发新型抗疟药已成为当前疟疾防治研究的迫切需求。随着恶性疟原虫基因组测序的完成和对疟原虫生物学认知的不断深入,寻找抗疟新靶点的研究得以快速发展。嘧啶生物合成途径是经临床确证有效的抗疟靶点的典范。我们简要综述了近年来以恶性疟原虫嘧啶从头合成途径第四步关键酶——二氢乳清酸脱氢酶(DHODH)为靶点的抗疟新药研究。高通量筛选、药物化学等研究已获得若干对恶性疟原虫DHODH有选择性抑制作用的化合物结构,其中有些在恶性疟原虫体外培养试验中表现出了较强的抗疟作用,且其酶抑制活性与抗疟活性间具有良好的相关性。通过三唑并嘧啶类系列先导化合物的优化研究,已获得了具有良好代谢稳定性、对鼠疟模型有效的类似物。已有大量研究表明DHODH靶向抗疟药的研发具有广阔前景。 展开更多
关键词 疟疾 疟原虫 嘧啶生物合成 二氢乳清酸脱氢酶 药物发现
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抑制二氢乳清酸脱氢酶的表达对线粒体功能的影响 被引量:2
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作者 方静娴 谢成婕 +2 位作者 谢远雯 黄馨 唐翔 《贵州医药》 CAS 2017年第8期795-799,共5页
目的探讨通过抑制二氢乳清酸脱氢酶(DHODH)的表达对线粒体功能状态的影响。方法采用siRNA沉默技术抑制宫颈癌HeLa细胞中DHODH的表达,检测细胞增殖、细胞周期状况和线粒体相应功能指标(线粒体膜电位和活性氧自由基)。结果 DHODH表达下调... 目的探讨通过抑制二氢乳清酸脱氢酶(DHODH)的表达对线粒体功能状态的影响。方法采用siRNA沉默技术抑制宫颈癌HeLa细胞中DHODH的表达,检测细胞增殖、细胞周期状况和线粒体相应功能指标(线粒体膜电位和活性氧自由基)。结果 DHODH表达下调后细胞增殖减缓(停滞于G2/M期),加入外源性尿苷虽可激活DHODH嘧啶合成反应旁路,却并不能缓解增殖减缓。DHODH缺失降低了线粒体膜电位(MMP)并使活性氧自由基(ROS)的产量增加,线粒体DNA数量减少。结论 DHODH在形成线粒体氧化呼吸复合物中发挥了相应的重要作用,对米勒综合征形成及线粒体调节细胞活力产生了重要影响。 展开更多
关键词 二氢乳清酸脱氢酶 嘧啶生物合成 线粒体功能障碍 泛醌 米勒综合征
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AtTHIC, a gene involved in thiamine biosynthesis in Arabidopsis thaliana 被引量:7
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作者 Danyu Kong Yuxing Zhu +3 位作者 Huilan Wu Xudong Cheng Hui Liang Hong-Qing Ling 《Cell Research》 SCIE CAS CSCD 2008年第5期566-576,共11页
Thiamine (vitamin B1) is an essential compound for organisms. It contains a pyrimidine ring structure and a thiazole ring structure. These two moieties of thiamine are synthesized independently and then coupled toge... Thiamine (vitamin B1) is an essential compound for organisms. It contains a pyrimidine ring structure and a thiazole ring structure. These two moieties of thiamine are synthesized independently and then coupled together. Here we report the molecular characterization of AtTHIC, which is involved in thiamine biosynthesis in Arabidopsis. AtTHIC is similar to Escherichia coli ThiC, which is involved in pyrimidine biosynthesis in prokaryotes. Heterologous expression of AtTHIC could functionally complement the thiC knock-out mutant of E. coll. Downregulation of AtTHIC expression by T-DNA insertion at its promoter region resulted in a drastic reduction of thiamine content in plants and the knock-down mutant thicl showed albino (white leaves) and lethal phenotypes under the normal culture conditions. The thicl mutant could be rescued by supplementation of thiamine and its defect functions could be complemented by expression ofAtTHIC cDNA. Transient expression analysis revealed that the AtTHIC protein targets plastids and chloroplasts. AtTHIC was strongly expressed in leaves, flowers and siliques and the transcription of AtTHIC was downregulated by extrinsic thiamine. In conclusion, AtTHIC is a gene involved in pyrimidine synthesis in the thiamine biosynthesis pathway of Arabidopsis, and our results provide some new clues for elucidating the pathway of thiamine biosynthesis in plants. 展开更多
关键词 ARABIDOPSIS E. coli ThiC AtTHIC THIAMINE pyrimidine biosynthesis vitamin B1
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Induction of Recombinant Uridine Phosphorylase and Its Application in Biosynthesis of Pyrimidine Nucleosides 被引量:1
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作者 丁庆豹 欧伶 +3 位作者 魏东芝 魏晓琨 许彦梅 张春艳 《Chinese Journal of Chemical Engineering》 SCIE EI CAS CSCD 2011年第1期122-127,共6页
Recombinant Escherichia coli pUDP,which overexpressed uridine phosphorylase(UPase),was constructed.0.5 mmol·L 1lactose had a similar induction effect as the commonly used inducer IPTG during 2.5-5.5 h of cell g... Recombinant Escherichia coli pUDP,which overexpressed uridine phosphorylase(UPase),was constructed.0.5 mmol·L 1lactose had a similar induction effect as the commonly used inducer IPTG during 2.5-5.5 h of cell growth.The lactose-induced UPase was stable at 50°C.Wet cells of pUDP was used as catalyst to biosynthesize 5-fluorouridine from 30 mmol·L 1uridine and 5-fluorouracil in phosphate buffer(pH 7.0)catalyzed at 50°C for 1.5 h and the yield of 5-fluorouridine was higher than 68%.Under the optimum reaction conditions for production of 5-fluorouridine,5-methyluridine and azauridine were synthesized from uridine by pUDP,the yield was 61.7%and 47.2%respectively.Deoxynucleosides were also synthesized by pUDP,but the yield was only about 20%. 展开更多
关键词 5-fluorouridine LACTOSE uridine phosphorylase pyrimidine nucleoside URIDINE 5-FLUOROURACIL
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Synthesis and Mollucicidal Activity of Some New Bicyclic and Polycyclic Pyrimidine Derivatives
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作者 Mohamed Abdel-Megid Mohamed Abdel-Hamid Awas +2 位作者 Magdy Seada Kamelia Mohamed Elmhdy Mortta Mohamed Elsayed 《Journal of Chemistry and Chemical Engineering》 2010年第5期41-53,共13页
Hydrazinolysis ofethylthiopyrimidine derivative 2 gave 2-hydrazinopyrimidine 3 which used as a convenient precursor for the synthesis of pyrazolylpyrimidines, hydrazones and pyrimidotriazines. Also, treatment of 2 wit... Hydrazinolysis ofethylthiopyrimidine derivative 2 gave 2-hydrazinopyrimidine 3 which used as a convenient precursor for the synthesis of pyrazolylpyrimidines, hydrazones and pyrimidotriazines. Also, treatment of 2 with ethyl chloroacetate yielded N^-carbethoxymethyl-2-ethylthio-pyrimidine 15, which on reaction with ethyl carbazate and hydrazine hydrate afforded pyrimidotriazine and imidazopyrimidine, respectively. Chlorination of 2 using phosphorous oxycbloride yielded 4-chloropyrimidine 18, which reacted with some heterocyclic compounds having vicinal amino cyano groups to give some new polynuclear heterocyclic system. Also, the effect of some active methylene compounds on 18 was also studied. Some of the newly synthesized compounds were tested as mollucicidal agents against Biomphlaria alexandrina snails that caused intestinal bilharzias, the national problem in Egypt. 展开更多
关键词 Pyrazolylpyrimidines pyrimidotriazines imidazopyrimidines pyrimidopyrimidines mollucicidal activity.
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Synthesis and antitumor activities of a new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives 被引量:2
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作者 GUO DeXiang LIU YaJing +4 位作者 LI Ting WANG Nan ZHAI Xin HU Chun GONG Ping 《Science China Chemistry》 SCIE EI CAS 2012年第3期347-351,共5页
A new series of 4,5-dihydro-lH-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized. The anti- tumor activities of the target compounds have been evaluated in vitro against two human cancer cel... A new series of 4,5-dihydro-lH-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized. The anti- tumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549 (human alveolar adenocarcinoma cell) and H460 (human lung cancer) by MTT assay. Most of the target compounds exhibited significant antitumor activities against A549 and H460 cancer cell lines. The most potent compound 4-(benzo[d][1,3]dioxol- 5-yl)-8,9-difluoro-2-(4-methylpiperazin-l-yl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH05) (IC50 = 0.44 μM, 3.07 μM) was 2.0 and 8.4 times more active than gefitinib (IC50= 0.89 μM, 16.81 μM) against A549 and H460 cell lines, respectively. 展开更多
关键词 HETEROCYCLE SYNTHESIS 4 5-dihydro-lH-thiochromeno[4 3-d]pyrimidine derivatives antitumor activity
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Biological evaluation of 2-methylpyrimidine derivatives as active pan Bcr-Abl inhibitors
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作者 ZOU DingBiao QIU YaTao +6 位作者 TU ZhengChao LIAO ChenZhong LUO JinFeng MENG QingQing YAO RiSheng LI Zheng JIANG Sheng 《Science China Chemistry》 SCIE EI CAS 2014年第6期823-832,共10页
We designed a series of 2-methylpyrimidine derivatives as new BCR-ABL inhibitors using scaffold-hopping strategy.These synthetic compounds exhibited significant inhibition against a broad spectrum of Bcr-Abl mutants i... We designed a series of 2-methylpyrimidine derivatives as new BCR-ABL inhibitors using scaffold-hopping strategy.These synthetic compounds exhibited significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I mutant.Compound 7u showed very potent kinase inhibitory activities against Bcr-Abl WT,Bcr-Abl E255K,Bcr-Abl Q252H,Bcr-Abl G250E and Bcr-Abl T315I,with IC50 values of 0.13 nM,0.17 nM,0.24 nM,0.19 nM and 0.65μM,respectively.This compound also displayed anti-proliferation activity against K562 cell line with an IC50 value of 1.1 nM,thus representing a new lead for further optimization. 展开更多
关键词 chronic myeloid leukemia(CML) anticancer agents BCR-ABL imatinib resistance
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