5-氟脲嘧啶-2′-脱氧核苷的试制

5-氟脲嘧啶-2′-脱氧核苷(FUDR)为一种抗代谢药物,可抑制胸腺嘧啶核苷合成酶,阻断脲嘧啶脱氧核苷转变为胸腺嘧啶脱氧核苷,影响DNA的生物合成,从而抑制肿瘤生长。用于治疗进行手术困难的肿瘤如直肠癌、结肠癌、胃癌、肝癌等。     

阿糖腺苷2′,5′-环磷酸酯和阿糖腺苷5′-亚磷酸酯的合成

为提高抗病毒药阿糖腺苷(Ara-A)的水溶性,合成了阿糖腺甘2′,5′-环磷酸酯,阿糖腺苷5′亚磷酸酯以及相应的酰基衍生物。抗病毒筛选结果表明,阿糖腺苷2′,5′-环磷酸酯在1μg/ml 浓度时对Ⅰ型单纯疱疹病毒有明显抑制作用。     

5′-RS-1，5-二氧代-（5′-乙基-5′-羟基-2′H，5′H，6′1-6-氧代吡喃）-[3′，4′，f]．Δ^6（8）-四氢中氮茚的合成工艺改进

目的 改进喜树碱关键中间体5′-RS-，5-二氧代-（5′-乙基-5′-羟基-2′H，5′H，6′H-6-氧代吡喃）-[3′，4′，f]-△^6（8）-四氢中氮茚（1）的合成工艺。方法 以6-氰基-1，1-亚乙二氧基-7-（1′-乙氧羰基）丙基-5-氧代-△^6（8）-四氢中氮茚（2）为原料，经氢化和亚硝化、脱氮、混合金属催化氧化、环合及三氟乙酸脱保护反应得到目标产物。结果与结论 新工艺简化了操作、缩短了反应时间，总产率达到了72．4％。     

用HPLC法分析2′-氟-2′,3′-二脱氧腺苷和2′-氟-2′,3′-二脱氧肌苷

2′氟2′,3′二脱氧腺苷(FddA)及其代谢物2′氟2′,3′二脱氧肌苷(FddI)具有抗HIV的活性。作者用HPLC法同时测定了狗血浆和尿中的FddA和FddI浓度。实验中的内标物质为3′,5′脱水胸苷(IS)。标准品的制备　含有FddA和FddI的血浆和尿标准品的标准曲线范围在血浆中为0.1～20μg·mL-1,在尿中为2～257μg·mL-1。3份血浆对照品(含FddA和FddI为1.0,15.2或50.8μg·mL-1)与2份尿样标准品(含FddA为36.0或366μg·mL-1,含FddI为42.0或420μg·mL-1)经制备后与供试样品一同分析。色谱条件　DuPontZorbaxC8柱(4.6mm×250mm,5μm粒径)…     

抗癌药5-氟尿嘧啶-2′-脱氧核糖核苷合成路线改进

本文介绍了由5′-尿嘧啶核糖核苷酸二钠盐,经化学法脱磷酸,得尿嘧啶核糖核苷,在无水乙腈中与丙酰溴反应,得3′,5′-二丙酰-2′-脱氧-2′-溴代尿嘧啶核糖核苷,催化氢化脱溴,得3′,5′-O-二丙酰基-2′-脱氧尿嘧啶核糖核苷,用氟氮混合气氟化,甲醇-氨水脱保护基,制得5-氟尿嘧啶-2′-脱氧核糖核苷的方法。起始原料为味精厂综合利用产品。     

N4-烷基-5-甲基-2′-脱氧胞苷的合成

3′,5′-O-二苯甲酰胸苷在三氯氧磷存在的条件下与1,2,4-三唑缩合可得到1-(3′,5′-O-二苯甲酰-β-D-呋喃核糖)- 4-(1,2,4-三唑-1-基)-5-甲基-嘧啶-2-(1H)-酮,再用不同的胺取代核苷C4上的三唑基团可制备一系列全新的N4-烷基取代的5-甲基胞苷.方法简便 ,收率高.     

2′-溴代-2′-脱氧-3′,5′-O-二丙酰基-β-D-核糖胸苷合成工艺的研究

目的改进2′-溴代-2′-脱氧-3′,5′-O-二丙酰基-β-D-核糖胸苷的合成工艺.方法以胸腺嘧啶和四乙酰核糖为原料,经过硅烷化保护、缩合、皂化、卤化反应合成.结果与其他文献方法比较,该法具有操作简单、收率高、成本低等特点.结论 适用于工业化生产.     

Antitumor cell and antimetabolic effects of 5-ethyl-2′-deoxyuridine and 5′-substituted 5-ethyl-2′-deoxyuridine derivatives

Summary A series of forty 5-ester derivatives of 5-ethyl-2-deoxyuridine (EDU) have been evaluated for their inhibitory effects on the growth and metabolism of murine leukemia L1210 cells. Several EDU esters proved as potent as EDU in their inhibitory effects on L1210 cell growth (inhibitory dose-50: 5–10 g/ml), suggesting that these esters were readily hydrolyzed to release the parent compound EDU. That the EDU esters had to be hydrolyzed first to EDU was further suggested by the dependence of their antiproliferative action on the thymidine kinase activity of the cells. It was further ascertained that EDU and its esters acquired their antiproliferative effects by an interaction with dCTP biosynthesis, possibly at the CDP ribonucleotide reductase step. Under conditions where thymidine was readily incorporated, we were unable to demonstrate any incorporation of EDU into L1210 cell DNA.     

Evaluation of Developmental Toxicity of Ultraviolet Absorber 2-(3′,5′-Di-tert-Butyl-2′-hydroxyphenyl)-5-Chlorobenzotriazole in Rats

2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as a UV absorber. In this study, the developmental toxicity of DBHCB was evaluated in rats. Pregnant rats were given DBHCB at 0, 62.5, 250, or 1000 mg kg^?1 day^?1 by gavage on days 5–19 of pregnancy. No deaths were observed in the pregnant rats of any group. No effect of DBHCB on the general conditions, body weight gain, or feed consumption was observed in the pregnant rats. There were no changes in the ovarian weight, gravid uterine weight, or necropsy findings in the maternal rats of the DBHCB-treated groups. No significant effects of DBHCB were found in the number of corpora lutea, implantations, live fetuses, resorptions or dead fetuses, incidence of pre- or postimplantation embryonic loss, viability of fetuses, fetal weight, or sex ratio of live fetuses. No significant difference in the incidence of fetuses with malformations or variations or degree of ossification was detected between the DBHCB-treated and control groups.     

N~6-2′-O-双丁酰-3′,5′-环化腺苷酸的生产

随着cAMP作用机理研究的深入,人们发现cAMP进入机体后很容易被磷酸二酯酶水解而失去作用的弊病。此外Posternak等人认为,由于cAMP分子具有一定的极性,影响进入细胞的能力。所以近几年来对cAMP衍生物的研究及试制开始引起人们的注意。迄今已合成的cAMP衍生物中大致不外乎以下几类:(1)N~6—NH_2部位的改变;(2)2'—OH的取代;(3)磷酰基的改变;(4)C—8的取代。而最早合成及使用最多的衍生物是N~6—2’—O—双丁酰环化腺苷酸(DBC),于1967年经Falbriard合成。我们在按Falbriard方法     

抗肿瘤药物2′-脱氧-5-氟尿苷合成研究

目的:合成抗肿瘤药物2′-脱氧-5-氟尿苷。方法:以5-氟尿嘧啶核苷为原料,经丙酰溴酰化溴代得2′-溴代-3,′5′-O-二丙酰基-5-氟尿嘧啶核苷,然后氢化得产物2′-脱氧-3,′5′-O-二丙酰基-5-氟尿嘧啶核苷,最后经皂化合成2′-脱氧-5-氟尿苷。结果:以5-氟尿嘧啶核苷为起始原料经3步反应合成了2′-脱氧-5-氟尿苷。结论:本合成方法工艺简便,原料易得,条件温和,总收率为72.0%,适于工业制备。     

2R-羟甲基-5S-(5′-氟胞嘧啶-1′-)-1,3-氧硫杂环戊烷的合成

报道2R-羟甲基-5S-（5′-氟胞嘧啶-1′-）-1,3-氧硫杂环戊烷（FTC）及其关键中间体 5R-乙酰氧基-1,3-氧硫杂环戊烷-2-羧酸（1′R，2′S，5′R）-薄荷酯的合成，并对文献报道的路线进行了改进，特别是避免使用昂贵而敏感的三甲基碘硅烷，易于工业化生产。     

5′-RS-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃)-[3′,4′,f]-Δ6(8)-四氢中氮茚的合成工艺改进

目的改进喜树碱关键中间体5′-RS-1,5-二氧代-(5′-乙基-5′-羟基-2′H,5′H,6′H-6-氧代吡喃) -[3′,4′,f]-Δ6(8)-四氢中氮茚(1)的合成工艺.方法以6-氰基-1,1-亚乙二氧基-7-(1′-乙氧羰基)丙基-5-氧代-Δ6(8)-四氢中氮茚(2)为原料,经氢化和亚硝化、脱氮、混合金属催化氧化、环合及三氟乙酸脱保护反应得到目标产物.结果与结论新工艺简化了操作、缩短了反应时间,总产率达到了72.4%.     

Gender-Related Difference in the Toxicity of Ultraviolet Absorber 2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole in Rats

2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as an ultraviolet absorber. Previously, we showed that male rats had more than a 100 times higher susceptibility to the toxic effects of DBHCB than females. In order to investigate the role of sex steroids in the mediation of this gender-related difference, DBHCB (0 or 250?mg/kg/day) was given to male and female young intact and castrated rats by gavage for 28 days in the current study. In intact rats, relative liver weight increased to more than two times that of the control in males, while the rate of change was less than 10% in females. On histopathology, hypertrophy of hepatocytes was observed in males but not in females. In castrated rats, an approximately 40% increase in the relative liver weight was found only in males, and no histopathological changes in the liver were detected in either sex. The gender-related difference was also determined in preweaning rats administered DBHCB at 0, 250, or 500?mg/kg/day by gavage from postnatal days 4 to 21. Blood biochemical changes, including increases in the levels of AST, ALT, and ALP, 80–95% increase in the relative liver weight and histopathological changes in the liver, such as hypertrophy and single cell necrosis of hepatocytes, were observed at both doses in both sexes. In conclusion, the gender-related difference in the toxicity of DBHCB, which was observed in young rats, was markedly reduced by castration and abolished in preweaning rats.     

查尔酮类天然产物2′,4′-二羟基-6′-甲氧基-3′,5′-二甲基查耳酮的研究进展

2′,4′-二羟基-6′-甲氧基-3′,5′-二甲基查耳酮(DMC)是一种来源于多种植物的查尔酮类天然产物,具有良好的药理活性。本文从理化性质、来源、提取与检测、化学合成、药理活性等方面对DMC的国内外研究进展进行综述,为DMC的前药设计和开发提供参考依据。     

Repeated-Dose and Reproductive Toxicity of the Ultraviolet Absorber 2-(3′,5′-Di- tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole in Rats

2-(3′,5′-Di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole (DBHCB) is widely used as an ultraviolet (UV) absorber. In this study, the repeated dose and reproductive toxicity of DBHCB was evaluated in rats. Crj:CD(SD)IGS rats were given DBHCB by gavage at 0, 2.5, 25, or 250 mg/kg/d. Male and female rats were dosed beginning 28 d before mating, and each female rat was mated with a male rat of the same dosage group. Males were dosed for a total of 56–57 d, and females were dosed for a total of 55–69 d up to Day 3 of lactation throughout the mating and pregnancy periods. Ten males from each group were killed on the next day of the last administration, and 10 females were killed on Days 4–6 after parturition. Five rats/sex treated at 0 and 250 mg/kg/d for 56 d were then kept without treatment for 14 d (recovery period). No deaths were found in any group. No effects of DBHCB on general condition, body weight, food consumption, or reproductive/developmental parameters were observed. Significant increases in serum albumin and an albumin/globulin ratio at 25 mg/kg/d and higher and alkaline phosphatase levels at 250 mg/kg/d were noted in males. The absolute and relative weights of the liver were significantly increased in males at 25 mg/kg/d and higher. Significantly increased serum albumin and absolute and relative liver weight were also found in males at 250 mg/kg/d after the recovery period. No changes in these parameters were observed in females of any DBHCB-treated groups. No significant changes in organ histopathology were found in males or females. These findings indicated a sex difference in the toxicity of DBHCB in rats.     

Brain Parenchymal Metabolism of 5-Iodo-2′-Deoxyuridine and 5′-Ester Prodrugs

In an attempt to generate derivatives of 5-iodo-2-deoxyuridine (IDU) with enhanced blood-brain barrier (BBB) permeability, a series of 5 ester prodrugs of IDU was synthesized and their metabolism studied in rat brain homogenate and its different subcellular fractions. The rate of hydrolysis was dependent on the steric and polar nature of the ester substituent. Ester hydrolyzing activities were associated primarily with the cytosolic fraction and were due mainly to the presence of cholinesterases as confirmed by inhibition experiments performed with different esterase inhibitors. The metabolism of IDU to 5-iodouracil (5-IU) by the cytosolic fraction, in the presence and absence of specific pyrimidine nucleoside phosphorylase inhibitors, also suggests that there are two specific enzyme systems catalyzing two different metabolic processes. IDU 5-esters competitively inhibit the metabolism of IDU and the inhibitory effect depends on the affinity of a particular ester toward the enzyme and also on the rate by which the ester itself undergoes hydrolysis. In the absence of any 5-ester, 95% IDU was metabolized within 6 hr. However, in the presence of an eightfold molar excess of butyryl-IDU, the hydrolysis of IDU was completely inhibited over a 6-hr time period.     

5′-脱氧-5-氟尿苷的细胞毒作用机制

5′-脱氧-5-氟尿苷(5′-FUdR)与氟尿嘧啶、氟尿苷、5-氟-2-脱氧尿苷或喃氟啶相比,其抗癌活性较高,其抗癌作用机理除与上述药物相似外,可在敏感肿瘤细胞中裂解为氟尿嘧啶而发挥作用,并无其他有毒代谢物产生。本文进一步阐明它对艾氏腹水癌细胞毒性作用的机理,结果如下。     

3-(2′-氯-6′-氟苯基)-5-甲基-4-异噁唑甲酰氯的合成

目的 研究抗生素氟氯西林钠的关键中间体3-(2'-氯-6'-氟苯基)-5-甲基-4-异噁唑甲酰氯的合成方法,使之适合工业化生产.方法 以2-氯-6-氟苯甲醛为原料,经肟化、氯化、环合、水解、酰氯化等步骤制得目标化合物.结果 合成产物的化学结构经IR,1H-NMR,13C-NMR and MS确证,总收率为60.2%.结论 此方法收率高,成本低,适合工业化生产.