含5－氟尿嘧啶的杂氮硅三环衍生物的合成

为了探求高效低毒新的抗癌药物，作者设计并合成了１０个不同结构的含５－氟尿嘧啶的杂氮硅三环衍生物，其结构经ＩＲ，１ＨＮＭＲ，ＵＶ和元素分析等证实。初步动物实验表明：某些化合物具有一定抗癌活性。     

含5—氟尿嘧啶的杂氮硅三环衍生物的合成

为了探求高效低毒新的抗癌药物，作者设计并合成了１０个不同结构的含５－氟尿嘧啶的杂氮硅三环衍生物，其结构经ＩＲ、＾１ＨＮＭＲ、ＵＶ和元素分析等证实，初步动物实验表明：某些化合物具有一定抗癌活性。     

10-羟基氮杂solamin类似物的合成及其生物活性

目的设计合成新型番荔枝内酯氮杂类似物,评价其抗肿瘤活性。方法以氮杂solamin为分子模型,运用生物电子等排原理,设计并合成10-羟基氮杂solamin类似物,并与前体化合物比较对HL-60、LoVo和HT-29肿瘤细胞株的生长抑制作用。结果该化合物未见文献报道,其结构经IR1、H-NMR及MS确证。结论所设计的氮杂类似物具有一定程度的抗肿瘤活性,羟基官能团对化合物抗肿瘤活性具有一定贡献。     

3,7,10-三甲基-γ-氨丙基杂氮硅三环衍生物的合成

目的设计合成新的3,7,10-三甲基-γ-氨丙基杂氮硅三环衍生物。方法以三异丙醇胺和γ-氨丙基三乙氧硅烷为原料,通过硅烷化、酰化、磺酰化、异氰酸酯化等反应合成目标化合物(1、2、3a～3c、4a～4d)。结果与结论合成了9个未见文献报道的新化合物,目标物的结构均经1H-NMR、IR、MS及元素分析确证。     

地西他滨的合成

2-脱氧-D-核糖在吡啶作用下与乙酐进行乙酰化,再在TMSOTf作用下与5-氮杂胞嘧啶偶联得1-（3,5-二-O-乙酰基-2-脱氧-D-核糖）-5-氮杂胞嘧啶,最后经氨气脱保护、甲醇重结晶得抗肿瘤药地西他滨,总收率约32%。     

抗癌剂的研究 Ⅱ.1-(四氢-2-呋喃基-5-氟尿嘧啶和1,3-双(四氢-2-呋喃基)-5-氟尿嘧啶的合成和抗肿瘤活性

5-氟尿嘧啶的衍生物1-(四氢-2-呋喃基)-5-氟尿嘧啶即呋氟尿嘧啶或FT207(3)系低毒且可供口服的抗肿瘤药物。本文报道呋氟尿嘧啶(3)和1,3-双-(四氢-2-呋喃基)-5-氟尿嘧啶(4)的简便合成法和实验抗肿瘤活性。     

5-氟尿嘧啶衍生物的合成与抗肿瘤活性研究

目的寻找新型、高效的5-氟尿嘧啶衍生物类抗肿瘤化合物。方法设计、合成4个5-氟尿嘧啶衍生物,利用MTT方法测定这些化合物对4株肿瘤细胞的增殖抑制活性。结果 4个5-氟尿嘧啶衍生物均显示了较好的肿瘤细胞增殖抑制活性。结论 4个目标化合物对肿瘤细胞有较好的抑制活性,值得进一步研究。     

吲哚美辛5-氟尿嘧啶甲酯的合成及抗肿瘤活性

目的合成吲哚美辛5-氟尿嘧啶甲酯,并对其体内外抗肿瘤活性进行评价。方法以5-氟尿嘧啶及吲哚美辛为主要原料,经2步反应合成目标化合物。应用Hela、HT1080、kB、Heps及Bel-7 402等5种肿瘤细胞系对吲哚美辛5-氟尿嘧啶甲酯体外抗肿瘤活性进行评价;选用小鼠肉瘤S180瘤株、肝癌H22瘤株和Lewis肺癌实体瘤3种瘤株为指标,对吲哚美辛5-氟尿嘧啶甲酯的体内抑瘤活性进行考察。结果经熔点测定及1H-NMR、MS及IR确证目标产物结构,产品收率为66%;吲哚美辛5-氟尿嘧啶甲酯的体外抗肿瘤作用很弱,但对于小鼠S180、H22及Lewis 3种实体瘤的抑制作用与5-氟尿嘧啶相近。结论吲哚美辛5-氟尿嘧啶甲酯为5-氟尿嘧啶的前体药物。     

合成药物

225.5-氟尿嘧啶的苯甲酰基及苯磺酰基衍生物的抗肿瘤活性5-氟尿嘧啶已在临床用于治疗各种实体肿瘤,但口服时对肠胃道有毒性。1-(2-四氢呋喃基)5-氟尿嘧啶(V,FT-207)口服给药对肠胃道的毒性较小。作者报导(Ⅰ)～(Ⅳ)对实验动物的抗肿瘤活性并与Ⅴ作了比较。     

3-全乙酰化半乳吡喃糖基-5-氟尿嘧啶的合成及其体外抗肿瘤活性研究

目的设计合成5-氟尿嘧啶半乳糖衍生物,并对其抗肿瘤活性进行评价。方法以5-氟尿嘧啶结构为基础,化学合成3-全乙酰化半乳吡喃糖基-5-氟尿嘧啶(3-PGF),采用质谱(MS)及核磁共振氢谱(1H-NMR)对其结构进行表征;MTT比色分析法比较3-PGF与5-FU作用于人结肠癌细胞(SW-1116)及正常人肠上皮细胞(HIEC)后,其对细胞生长抑制率的差异。结果 MS和1H-NMR的结果确证合成化合物为目标产物;体外实验结果表明,3-PGF(0.01～100μmol.L-1)作用于SW-1116细胞48 h后,其对细胞的生长抑制率为8.45%～65.53%,呈浓度依赖性。在HIEC细胞中,3-PGF的细胞生长抑制作用明显低于5-FU。结论本实验成功合成了5-氟尿嘧啶半乳糖衍生物——3-全乙酰化半乳吡喃糖基-5-氟尿嘧啶,不仅具有较好的抗肿瘤活性,同时,该衍生物的毒性明显低于5-FU,为5-FU衍生物的设计合成提供了新的思路。     

含5－FU的杂氮硅三环衍生物抗瘤活性及吞噬活性的测定

观察含５－ＦＵ的杂氮硅三环衍生物Ⅴ对小鼠肉瘤Ｓ－１８０及ＥＳＣ的抑瘤活性及其对荷瘤小鼠吞噬功能的影响。结果表明：化合物Ⅴ对小鼠Ｓ－１８０，ＥＳＣ抑瘤率分别可达６７．１％，５６．７％，并能增强荷瘤小鼠腹腔吞噬细胞的吞噬功能，其吞噬百分率与吞噬指数与对照组相比差异均有显著意义。     

含5－FU的杂氮硅三环衍生物抗瘤活性及吞噬活性的测定

观察含５－ＦＵ的杂氮硅三环衍生物Ⅴ对小鼠肉瘤Ｓ－１８０及ＥＳＣ的抑瘤活性及其对荷瘤小鼠吞噬功能的影响。结果表明：化合物Ⅴ对小鼠Ｓ－１８０，ＥＳＣ抑瘤率分别可达６７．１％，５６．７％，并能增强荷瘤小鼠腹腔吞噬细胞的吞噬功能，其吞噬百分率与吞噬指数与对照组相比差异均有显著意义。     

From a classic approach in cancer chemotherapy towards differentiation therapy: acyclic and cyclic seven-membered 5-fluorouracil O,N-acetals

Novel derivatives of 5-fluorouracil (5-FU) possessing a broader spectrum of antitumor activity and fewer toxic side effects than 5-FU have been sought. Herein, we report three different types of 5-FU O,N-acetals: a) a novel class of 5-fluorouracil-containing acyclonucleosides. The antitumor activities of such compounds were assessed against HEp human cells showing that (RS)-1-?[3-(2-hydroxyethoxy)-1-cyclopentoxy]propyl?-5-fluorouracil 3c is 4-fold more active than 5-FU. (RS)-1-?[3-(2-hydroxyethoxy)-1-isopropoxy]propyl?-5-fluorouracil 3b has important potential advantages over 5-FU because of its lower toxicity and its ability to induce myogenic differentiation in rhabdomyosarcoma cells. Our results suggest that this drug may be useful for differentiation therapy in this type of tumor; b) within the cyclic prodrugs of 5-FU, a series of new ring-expanded isosteres (1,4-oxaheteroepanes) of Ftorafur were synthesized. The level of diastereoselectivity in the preparation of cis and trans 1-(3-chloromethyl)-1,4-dioxepan-5-yl)-5-fluorouracil, although modest, suggests a potentially general approach for controlling the stereochemistry of this unexplored class of reactions involving the preparation of 5-FU seven-membered O,N-acetals; c) new 5-FU acyclic analogs containing two 5-FU moieties at both ends of the molecules with a linker having two amide bonds have been designed and synthesized. These bis(5-FU-O,N-acetals) show interesting antineoplastic activities against the HT-29 cell line.     

含1，3，4-噻二唑的5-氟尿嘧啶衍生物的合成及其抗肿瘤活性

目的 制备低毒、高抗瘤活性的N<,1>-乙酰氨基-(5-烃基/芳基-1,3,4-噻二唑-2-基)-5-氟尿嘧啶衍生物.方法 以5-氟尿嘧啶为原料,在氢氧化钾的作用下与氯乙酸反应后,与合成的中间体2-氨基-5-取代-1,3,4-噻二唑反应制得目标物,并评价其抗肿瘤活性.结果 和结论 合成了7个未见文献报道的目标物3 a～3 g,并用<'1>HNMR、HRMS、IR确认了结构;目标化合物3 d、3 f和3 g有较好的抗肿瘤活性.     

脑靶向N_1-羧酰-5-氟尿嘧啶系列化合物体外透过血脑屏障抑制肿瘤细胞活性

目的研究已合成的N1-羧酰-5-氟尿嘧啶系列化合物体外透血脑屏障抑制人星形胶质瘤细胞的活性。方法利用台盼蓝染色显微镜法观察计数方法考查N1-羧酰-5-氟尿嘧啶系列前体药物体外对人星形胶质瘤细胞增殖活性抑制作用;并通过培养大鼠脑毛细血管内皮细胞,建立体外模拟血脑屏障模型,观察N1-维甲酰-5-氟尿嘧啶和N1-山梨酰-5-氟尿嘧啶体外透过血脑屏障模型对人星形胶质瘤细胞增殖活性抑制作用。结果该系列化合物抗人星形胶质瘤活性较5-氟尿嘧啶增强,而对大鼠脑毛细血管内皮细胞的毒性降低;N1-维甲酰-5-氟尿嘧啶和N1-山梨酰-5-氟尿嘧啶较5-氟尿嘧啶透过BBB抑制人星形胶质瘤细胞的作用更好。结论N1-羧酰-5-氟尿嘧啶系列化合物抗人星形胶质瘤活性及透过体外血脑屏障能力都较5-氟尿嘧啶好。     

N1-(芳)烷酰氧亚甲基-5-氟尿嘧啶的合成及其初步抗肿瘤活性的研究

目的　合成抗肿瘤活性高 ,毒性小的N1- (芳 )烷酰氧亚甲基取代的 5 -氟尿嘧啶衍生物。方法　以 5 -氟尿嘧啶为原料 ,经与甲醛加成反应后 ,和二酸单苄酯反应即得目标物 3a、3b、3c ,并采用MTT法及SRB法评价目标物 3的抗肿瘤活性。结果　合成了 3个目标物 3a、3b、3c ,其结构经1HNMR、IR和MS确证。结论　体外抗肿瘤活性筛选结果显示 3b和 3c有较强的抗肿瘤活性。     

Cytotoxic potency and induced biochemical parameters in mice serum of new furan derivatives against liver cancer cell line

On the basis of monitoring the inhibition of the growth of human cancer cells, a series of novel furan derivatives of possessing a broader spectrum of antitumor activity and fewer toxic side effects than traditional anticancer drugs have been studied. Ten selected furan derivatives were subjected to a screening system for investigation of their antitumor potency against liver (HEPG2) cell line. Moreover, the biochemical effects of the selected furan derivatives on some enzymes such as aspartate and a lanine aminotransferases (ASTand ALT) and alkaline phosphatase (ALP), in addition to albumin, globulins, creatinine, total lipids, cholesterol, triglycerides and bilirubin in serum of mice were studied in comparison to 5-fluorouracil and doxorubicin. The antitumor activity results indicated that the selected furan derivatives showed growth of inhibition activity against the tested cell line but with varying intensities extents. Results of the biochemical investigations indicated that 5-fluorouracil and doxorubicin caused significant changes in the level of all parameters tested while treatment with the selected compounds showed slight, moderate or no significant changes.     

Studies of antitumor agents. 1. Resolution of racemic 1-(tetrahydro-2-furanyl)-k-fluorouracil into the R and S isomers and examination of the biological activities of the isomers.

1-(Tetrahydro-2-furanyl)-5-fluorouracil (Thf-FU), which is named Ftorafur or FT-207 and is used clinically as an antitumor agent, was conveniently synthesized by condensation of the trimethylsilyl derivative of 5-fluorouracil with 2-acetoxytetrahydrofuran using NaI as a catalyst. This optically inactive Thf-FU was resolved into optically active (R)-(+)- and (S)-(-)-Thf-FU in high optical purity and excellent yield by formation of diastereoisomers with brucine. 13C NMR data were obtained on Thf-FU and related compounds and the antibacterial activities and in vivo antitumor activities of these isomers were tested. The degradations of these isomers to 5-fluorouracil by liver microsomes were also examined. No significant differences were found in any of these properties of these isomers.     

Novel derivatives of 5-fluorouridine and 5-fluorouracil having potent antitumor and lower immunosuppressive activities.

We studied the biological activities of several 5-fluorouridine (5-FUR) and 5-fluorouracil (5-FU) derivatives to find novel antitumor drugs with lower immunosuppressive effects. We examined 5-FUR and 5-FU derivatives acylated with (2-n-propyl-n-pentanoyl)glycine (KN-539). Among the examined compounds, we found satisfactory activities in a derivative of 5-FUR, 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21), and a derivative of 5-FU, 1-(6-[N-(2-n-propyl-n-pentanoyl)glycyl] amino-n-hexylcarbamoyl)-5-fluorouracil (UK-25). UK-21 (0.05-0.2 mmole/kg, p.o., 10 days) and UK-25 (0.1-0.4 mmole/kg, p.o., 10 days) suppressed Meth A and E.L.4 tumor growths in the corresponding syngeneic hosts (BALB/c mice and C57BL/6 mice, respectively) without decreasing body weight and blood leukocyte count. UK-21 and UK-25 suppressed the proliferation of KB tumor cells in vitro (IC50: 3.0 x 10(-11) M and 4.4 x 10(-7) M, respectively) at concentrations almost equivalent to those of 5-FUR and 5-FU, respectively. These results suggest that UK-21 and UK-25 express their antitumor activity as 5-FUR and 5-FU, respectively. Neither UK-21 nor UK-25 suppressed thymus weight and humoral antibody production against sheep red blood cells (SRBC) in ddY mice, although 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and 5-FU suppressed them in their respective therapeutic dose ranges for tumors. Thus, UK-21 and UK-25 are expected to develop into anticancer drugs with lower immunotoxicological effects.