高分子药物研究——Ⅱ.主链含5-氟脲嘧啶聚酯的合成

本文报道主链含5-氟脲嘧啶聚酯的合成及抗动物肿瘤初步试验。将5-氟脲嘧啶在二甲基甲酰胺中与无水碳酸钾作用,所生成的5-氟脲嘧啶钾盐随即与双氯乙酸二醇酯进行共缩聚,得到了6种主链含5-氟脲嘧啶的聚酯。同时还合成了三种新的双氯代乙酸二醇酯单体。     

载有5-氟脲嘧啶高分子药物的合成、结构及性能的研究

用可溶性淀粉或羧甲基纤维素作载体,合成了侧链连有5-氟脲嘧啶的四个系列的高分子载体药物;用分子筛作催化剂合成了两种新的5-氟脲嘧啶衍生物,利用IR、¹HNMR和质谱确定了它们的结构;研究了高分子药物含氮量随反应条件的变化规律及对其特性粘度的影响;并模拟生理条件在不同pH的缓冲溶液中对5-氟脲嘧啶的水解释放率进行了系统考查,对个别淀粉衍生物进行了生物活性测定。     

结肠靶向偶氮高分子的合成及其体外降解性能

以二环己基碳酰亚胺/N,N-二甲基氨基吡啶为偶联剂,将结肠前体药物5,5′-偶氮二水杨酸(奥沙拉秦)与生物相容的聚乙二醇缩聚,制备得到主链含偶氮键的聚乙二醇-奥沙拉秦(PEO-OLZ)缩聚物.研究表明,改变聚乙二醇链段的分子量,可以方便地调节偶氮缩聚合物的亲水性和生物降解性能.在动物盲肠液中所含的偶氮还原酶的作用下,PEO-OLZ缩聚物的偶氮键发生特异性降解,同时通过酯键的水解,释放出抗结肠炎药物5-氨基水杨酸.该类新型偶氮缩聚物可以作为结肠靶向聚合物前体药,亦可用作结肠定位控释的高分子载体.     

两种新型抗癌药的结构鉴定

本文应用质谱、核磁共振波谱、红外光谱及元素分析等方法对1-(2-四氢呋喃)-5-氟脲嘧啶(FT-207)和1,3-双(2-四氢呋喃)-5-氟脲嘧啶(FD-1)两种新型抗癌药进行了结构鉴定。     

苯烷基、对氯甲基苯烷基硅化合物的合成及其聚合物的热稳定性研究

通过相应烯烃的硅氢化反应,合成了-(CH_2)_n-SiX_3(n=2,3,4;X=Cl.OCH_3)及ClCH_2-(CH_2)_NSiX_3(n=2.3;X=Cl.OCH_3)等两类新型有机硅化合物.比较了它们水解缩聚产物的热稳定性.结果表明,所合成的两类硅单体均具预定的化学结构.在H_2PtCl_6-P(C_6H_5)_3的催化下,硅氢化反应系按反-马尔可夫尼科夫规则进行.另外,这两类有机硅单体的水解缩聚产物的热稳定性与芳基的位置(β、γ或δ位)有关而以在β位的为最高.     

聚西夫碱型共轭高分子的合成及电性能的研究

从乙二醛、对苯二醛与二元胺反应得到八种线型共轭结构的缩聚物。在模型化合物及其对应的聚合物的紫外、可见吸收光谱显示出随分子共轭程度的增加向长波位移。乙二醛与对苯二胺的缩聚物热处理后使结构芳香化,而对苯二醛与对苯二胺缩聚物在350℃以下热处理时,仍发生进一步缩聚反应。缩聚物的导电性能与分子的共轭程度及分子间的结构有关。     

芴-氮杂萘酮-聚芳醚酮离聚物的合成与性能

以双酚芴、双酚A型二氮杂萘酮、二氟二苯酮和二氟二苯酮磺酸钠为原料, 通过调整4种单体的比例以及加料顺序控制缩聚反应, 制备了一系列具有不同离子交换容量的含芴和二氮杂萘酮联苯单元的嵌段聚芳醚酮, 简称芴-氮杂萘酮-聚芳醚酮离聚物. 采用黏度测试、傅里叶衰减全反射红外光谱(FTIR-ATR)、氢谱(1H NMR)和热失重(TGA)等分析方法, 对不同结构的芴-氮杂萘酮-聚芳醚酮离聚物的分子量、结构及热稳定性进行了表征. 实验结果表明, 采用控制缩聚法能够制备出不同离子交换容量的高分子量芴-氮杂萘酮-聚芳醚酮离聚物, 该系列离聚物具有良好的热稳定性. 对该系列离聚物膜进行了抗氧化性、水解稳定性、吸水率、耐醇性、离子交换容量和质子传导率测试. 测试结果表明, 该系列离聚物具有良好的抗氧化性、水解稳定性、耐醇性、质子传导率和适当的吸水率.     

侧链含5-氟尿嘧啶甲壳胺的合成及其抗肿瘤活性的研究

本文报道了以不同分子量的甲壳胺为载体,制备了侧链含5-氟尿嘧啶的一系列高分子载体药物;通过定氮分析测定了H_2N-基的反应率;由IR、UV和~(13)C-NMR确定了载体药物的结构;模拟生理条件考查了在不同pH的缓冲溶液中5-氟脲嘧啶或其衍生物的水解释放率。体外初步实验结果表明,具有Ⅰ和Ⅱ结构的载体药物对艾氏腹水癌细胞有较强的杀伤作用。     

氮杂冠醚或吗啉基取代的单Schiff碱配合物催化α-吡啶甲酸对硝基苯酯水解

两种含5-取代苯并-10-氮杂-15-冠-5的Schiff碱锰(III)、钴(II)配合物( , )及其吗啉基取代的类似物( , ) 用于催化α-吡啶甲酸对硝基苯酯(PNPP)水解。探讨了氮杂冠醚Schiff 碱配合物催化PNPP水解的动力学和机理;提出了配合物催化PNPP水解的动力学模型;考察了配合物结构、反应温度、缓冲溶液pH值等对PNPP水解反应的影响。结果表明,在25℃条件下随着缓冲溶液pH值的增大,催化PNPP水解速率提高;含取代苯并-10-氮杂-15-冠-5的Schiff碱配合物表现出更高的催化活性。根据阿累尼乌斯公式和不同温度下的表观一级常数求出水解反应的表观活化能。     

5-氟脲嘧啶的D-氨基葡萄糖衍生物的合成及其抗肿瘤活性的研究

以α-氨基酸为连接基,将5-氟脲嘧啶同D-氨基葡萄糖键连合成了4种新的5-氟脲嘧啶的衍生物,并确认了它们的结构。体外抗肿瘤活性实验结果表明:链连的D-氨基葡萄糖使5-氟脲嘧啶的抗肿瘤活性有明显的提高,表明它们之间可能存在着某种抗肿瘤的协同作用。     

含5-氟脲嘧啶齐聚物的合成

<正> 5-氟脲嘧啶是用于治疗肺癌、肾癌、乳癌、结肠癌等癌变的药物。虽然5-氟脲嘧啶具有上述疗效,但在临床应用时,尚存在恶心,呕吐,腹泻,白细胞、血小板下降等副作用。更为严重的缺点,是既对肿瘤细胞有活性,同时也作用于正常细胞,为克服此缺点,将抗癌药物与低分子化合物结合,诸如激素、磺胺,这些是已知能集聚在一定组织内药物,但利用此法,迄今也很少获得成效。     

SYNTHESIS OF OLIGOMERS CONTAINING 5-FLUOROURACIL

The condensation oligomers of 5-fluorouracil were prepared by reaction of 2,4-bis-(trimethyl-silyloxy)-5-fluoropyrimidine) with various dicarboxylic chlorides, e.g.The structures of obtained oligomers were characterized by IR and the oligomers were then hydrolyzed in acid, alkaline and neutral media at room temperature respectively. The amount of 5-fluorouracil released was quantitated by measuring its UV absorbance at 265.5nm. However in the case of oligomers containing phenylene moiety, 5-fluorouracil was not detected when the hydrolysis was conducted in acid or neutral medium, while in the case of oligomers containing methylene moiety, hydrolysis proceeded easily in acid, alkaline and neutral media.     

CHEMOTHERAPEUTIC POLYMERS. THE SYNTHESIS OF POLYMERS CONTAINING 5-FLUOROURACIL IN THE MAIN CHAIN

1,3-Dialkyl-5-fluorouracil compounds and polymers containing 5-fluorouracil in the main chain were synthesized by the reaction of 5-fluorouracil with alkylbromidcs and polymethylene bromides respectively. The structures of the new compounds and polymers were confirmed by IR and NMR spectra as well as elemental analyses.The factors affecting the polycondensation, such as the temperature and time of the reaction were investigated. The anti-tumor activity of some of the 5-fluorouracil containing compounds and polymers were also measured.     

高分子药物研究——ⅩⅦ. 二羟烷基嘧啶与N,N’-双(2-氯乙基) 二氯磷酰胺缩聚物的合成及其抗肿瘤活性研究

本文通过七种二羟烷基嘧啶单体与N,N’一双(2-氯乙基)氯磷酰胺进行缩聚反应,制得了七种新的含核酸碱基或其类似物和氮芥的聚磷酸酯,用核磁、红外光谱及元素分析确定了单体和聚合物的结构。部分聚合物试验结果表明,既含氮芥又含5-氟尿嘧啶的聚合物具有较高的抗癌活性和较低的毒性,聚合物(Ⅲ_a)对小鼠艾氏腹水癌的抑制率可达66％。     

γ-核酸碱基取代丙基甲基二乙氧基硅烷的合成及其聚合反应研究

本文以Υ-溴丙基甲基二乙氧基硅烷分别与尿嘧啶、胸腺嘧啶、腺嘌呤和5-氟尿嘧啶进行烷基化反应,制得了四种含有核酸碱基或5-氟尿嘧啶的新型有机硅单体。通过它们的缩聚反应,合成了六种侧基含核酸碱基或5-氟尿嘧啶的聚硅氧烷。     

高分子药物研究Ⅸ.1,3-二羟烷基-5-氟尿嘧啶与二氯磷酸酯缩聚物的合成

<正> 核酸的抗代谢物是研究正常细胞和肿瘤细胞代谢、发展新的抗肿瘤药物的极好来源。近年来合成含核酸碱基、核酸碱基衍生物的聚合物引起了人们的极大兴趣。在这些聚合物中,核酸碱基及其衍生物均以侧基支载在聚合物上。我们将5-氟尿嘧啶引入不同化学结构的高分子主链上,合成了一系列高分子抗癌药物,经动物试验和一期临床观察     

A study of the stability of pyrimidine series cytostatics,Ftorafur and 5-fluorouracil: The effect of oxidation on the stability of Ftorafur and 5-fluorouracil

The stability of 1% solutions of cytostatics Ftorafur and 5-fluorouracil was studied during oxidation with hydrogen peroxide in alkaline (0.1 N NaOH), acidic (0.1 N H₂SO₄), and weakly acidic (pH 5) solutions by thin-layer chromatography. The decrease in the cytostatic content was monitored spectrophotometrically in the uv region. The greatest decrease in the cytostatic content occurred in alkaline solutions, where the pyrimidine ring opened between N3 and C4 and between C6 and N1, with formation of urea.     

CHEMOTHERAPEUTIC POLYMER ⅩⅦ. THE SYNTHESIS AND ANTITUMOR ACTIVITY OF POLYPHOSPHATES CONTAINING BOTH NUCLEIC ACID BASE AND NITROGEN MUSTARD

Seven new polyphosphates containing both nucleic acid base and nitrogen mustard were preparedby reacting the monomers, i.e. 1,3-dihydroxyalkyl-5-fluorouracil(II_(a.,b, g)), 1,3-dihydroxyalkyluracil(II_(c,d)) and 1, 3-dihydroxyalkylthymine (II_(e,f)) with W, N,N-bis(2-chloroethyl)phosphoramide dichlo-ride (I). The monomers and polymers were characterized by ~1H-NMR, IR spectra and elementalanalysis. All of the polymers obtained are soluble in water. The antitumor activity of some of thesepolymers were tested against Ehrlish Ascites in mice. The results showed that the polyphosphatescontaining both 5-fluorouracil and nitrogen mustard exhibit lower toxicity and higher antitumor ac-tivity. The inhibition ratio of the polymer (III_a) is 66%.     

Synthesis and characterization of ramose tetralactosyl-lysyl-chitosan-5-fluorouracil and its in vitro release

In order to improve drug loading and achieve a good release effect, this paper adopts the ramose method, choosing chitosan as the carrier and 5-fluorouracil (5-Fu) as a model drug. Ramose chitosan-lysyl-5-Fu(3) and ramose tetralactosyl-lysyl-chitosan-5-Fu(6) were synthesized successfully, then the in vitro release of (6) was researched. The results show that the drug loading of (3) and (6) are 9.17 and 1.63% (w/w), respectively. The in vitro release behavior of (6) in pH 7.4 phosphate buffer solution and pH 1.2 HCl?CKCl solution were studied. The zero order release time that (6) maintains in alkaline and acidic media are 64 and 24?h, and the total release by 184?h are 71.97 and 82.34%, respectively. The performance is smooth throughout the whole stage of release, and the concentration of cumulative release is lower in the alkaline environment than in the acidic environment over the same time.