吡啶丙烯酰氨基酸衍生物的设计、合成及其对离体HeLa-S3细胞的放射增敏作用

本文设计、合成了一类新型的放射增敏剂—吡啶丙烯酰氨基酸衍生物,并测定了对HeLa-Sa细胞的增敏作用和细胞毒性。3-吡啶丙烯酰甲基甘氨酸(3A)和4-吡啶丙烯酰甲基甘氨酸(4A)的主要作用分别为减小细胞存活曲线的肩宽和Do值。这类化合物,尤其是3A和4A,或其结构类似物,如果体内实验证明有明显增敏作用,将有重要的潜在临床应用价值。     

吡啶丙烯酸衍生物的合成及放射增敏作用的研究

目的:合成新化合物N-[3-(3-吡啶基)丙烯酰基]-2-氨基丁酸并观察其对HeLa细胞在有氧和乏氧条件下的毒性及放射增敏作用。方法:以3-吡啶丙烯酸和2-氨基丁酸乙酯盐酸盐为原料合成出N-[3-(3-吡啶基)丙烯酰基]-2-氨基丁酸,用噻唑蓝比色法(MTT实验)测定不同浓度化合物的细胞存活分数及其20%抑制浓度,运用集落形成实验测定放射增敏比。结果:合成出N-[3-(3-吡啶基)丙烯酰基]-2-氨基丁酸,总收率为78%,MTT实验测得其对有氧条件下HeLa细胞的20%细胞死亡所需药物浓度(IC20)为1.66mmol/L,乏氧条件下IC20为1.32mmol/L,通过集落形成实验得到有氧放射增敏比为1.44,乏氧放射增敏比为1.84。结论:N-[3-(3-吡啶基)丙烯酰基]-2-氨基丁酸合成方法简便,对体外HeLa细胞毒性较小,具有一定的放射增敏作用。     

新型抗肿瘤组蛋白去乙酰化酶抑制剂西达本胺的合成

目的:合成西达本胺{N-(2-氨基-5-氟苯基)4-[N-(吡啶-3-丙烯酰)氨甲基]苯甲酰胺}.方法:以吡啶甲醛为起始原料,通过Knoevenagel反应,制得吡啶丙烯酸,然后以N,N′-碳酰二咪唑(CDI)为催化剂,通过2步酰化反应,合成目标产物.结果:目标产物的产率为29%.结论:本法条件温和,操作简便,适合工业化生产.     

3-硝基-1,2,4-三唑类乏氧细胞放射增敏剂的构效关系

为了寻找毒性低、增敏作用强的乏氧细胞放射增敏剂,设计并合成了一系列5-溴-,5-甲基-,和5-未取代的3-硝基-1,2,4-三唑-1-乙酰胺类化合物,用HeLaS3细胞进行了体外试验。结果表明5-溴取代衍生物的增敏作用强于相应的5-甲基-或5-未取代的硝基三唑衍生物,但是它们的毒性亦增大。修饰1位乙酰胺侧链也可以改变化合物的增敏作用和亲脂性。在所测定的化合物中TA-101[2-(3-硝基-1-三唑基)乙酰胺]由于有高的增敏作用和低亲脂性,可能是一个有希望的放射增敏剂。     

甲磺酸伊马替尼的合成

用3-乙酰吡啶(2)和N,N-二甲基甲酰胺二甲缩醛(3)反应得3-二甲胺基-1-(3-吡啶基)-2-丙烯-1-酮(4),4与2-甲基-5-硝基苯基胍硝酸盐(6)经成环、还原、由4-氯甲基苯甲酰氯酰化后与N-甲基哌嗪反应,所得伊马替尼再成盐即得甲磺酸伊马替尼,总收率约58％(以2计).     

血吸虫病化学治疗的研究 Ⅱ.α-取代-β-(5-硝基-2-呋喃)丙烯酰胺及酯类衍生物的合成

本文报导α-取代-β-(5-硝基-2-呋喃)丙烯酰胺及酯类衍生物85个的合成。这类化合物系分别以糠醛或硝基糠醛与相应的羧酸钾盐经Perkin反应缩合后,按一般方法制成酰胺及酯;或以相应的硝基呋喃丙烯酰胺经溴化;或通过氮内酯中间体经水解、醇解和氨解而制备。经动物篩选后发现有13个化合物对感染日本血吸虫小白鼠有作用,其中α—甲基—β-(5-硝基-2-呋喃)丙烯酰正丁胺(I_6,F-30058),α-甲基-β-(5-硝基-2-呋喃)丙烯酰乙醇胺(I_(10),F-30141)及α-甲基-β-(5-硝基-2-呋喃)丙烯酰-2′-羟基丙胺(I_(11),F-30111)三个具有较好抑制作用。     

关于血吸虫病化学治疗的研究Ⅰ.β-(5-硝基-2-呋喃)丙烯酰胺及其酯类衍生物的合成

本文报导合成了硝基呋喃丙烯酰胺及其酯类衍生物107个.这类化合物的合成是从糠醛經Perkin反应制备β-呋喃丙烯酸,然后硝化成β-(5-硝基-2-呋喃)丙烯酸,再經酰氯与相应的胺类或氨基酸等縮合为酰胺。酯类则直接用酸与相应的醇酯化而得.經动物篩选后发現其中有33个化合物对感染日本血吸虫病小白鼠有显著作用.尤以β-(5-硝基-2-呋喃)丙烯酰异丙胺(I_4,F-30066)及β-(5-硝基-2-呋喃)丙烯酰甘氨酸乙酯(Ⅵ_(17),F-30069)具有强烈杀虫效力,均已試用于临床,証明有一定疗效。     

3,5-甾二烯化合物的合成及抗早孕活性

以18-甲基-17β-羟基-17α-乙炔基-雌甾-4-烯-3-酮(18-甲基炔诺酮),17β-羟基-17α-乙缺基-雌甾-4-烯-3-酮(炔诺酮),17β-羟基-17α-乙炔基-雄甾-4-烯-3-酮(妊娠素)和17a-羟基孕甾-4-烯-3,20二酮(17α-羟基黄体酮)为原料,经NaBH,还原、脱水、双键转位和酯化等反应合成一系列3,5-甾二烯化合物,用¹HNMR和MS证明了它们的结构。动物筛选结果表明,17β-丙酰氧基-17α-乙炔基-雌甾-3,5-二烯(IV_b2有明显的抗早孕活性。中断早期妊娠的作用似与其雌激素活性有关。     

茚并吡啶类衍生物诱导HEp-2细胞凋亡

目的:探讨1-甲基-5-(4-二甲氨基苄烯)-5H-茚[1,2b]吡啶三氟甲磺酸盐(受试物)对人喉表皮样肿瘤细胞HEp-2的增殖抑制和凋亡诱导作用。方法:采用MTT法观察受试物对HEp-2增殖的抑制作用,Hoechst 33258荧光染色观察HEp-2细胞凋亡形态学变化,流式细胞仪PI单染法检测细胞周期及凋亡率,采用Western Blot分析检测促凋亡蛋白Bid的表达。结果:1-甲基-5-(4-二甲氨基苄烯)-5H-茚[1,2b]吡啶三氟甲磺酸盐可抑制HEp-2细胞的增殖,并呈时间和剂量依赖性;用受试物(4μmol.L-1)处理细胞(24和48 h),经Hoechst 33258荧光染色,可见细胞凋亡形态学改变;流式细胞仪检测显示,HEp-2细胞周期发生改变,凋亡率增加;Western Blot分析结果显示,受试物可使促凋亡蛋白Bid表达水平上升。结论:1-甲基-5-(4-二甲氨基苄烯)-5H-茚[1,2b]吡啶三氟甲磺酸盐可抑制HEp-2细胞增殖,诱导其凋亡。     

醋酸麦迪霉素(Midecamycin Acetate)

异名 Miocamycin,Miocamicin,Mi-okamycin,Miocamen,MoM 化学名 (4R,5S,6S,7R,9R,10R,11E13E,16R)-10-乙酰氧基-6-[[3,6-二脱氧-4-O-(3-O-乙酰-2,6-二脱氧-3-C-甲基-4-O-丙酰-α-L-核型-已吡喃糖基)-3-(二甲基氨基)-β-D-吡喃葡糖基]氧]-5-甲氧基-9,16-二甲基-4-丙酰氧基-2-氧代氧杂环十六碳-11,13-二烯-7-乙醛     

Hypoxia-selective antitumor agents. 6. 4-(Alkylamino)nitroquinolines: a new class of hypoxia-selective cytotoxins.

A series of isomeric 4-[[3-(dimethylamino)propyl]amino]nitroquinolines has been synthesized and evaluated as hypoxia-selective cytotoxins and as radiosensitizers of hypoxic cells. The compounds showed widely-differing hypersensitivity factors (ratios of cytotoxicity against wild-type and repair-deficient mammalian cells). Many compounds showed oxygen-sensitive bioreduction resulting in DNA alkylation, while others show oxygen-insensitive modes of action. Of the nitro isomers studied, the 5-nitro showed the greatest hypoxic selectivity. A series of ring-substituted analogues were then prepared, in an effort to lower its reduction potential of -286 mV. Structure-activity studies showed that the effects of substitution on reduction potential were complex, being mediated by electronic and steric effects on the nitro group, as well as by effects on quinoline pKa. Two compounds of lower reduction potential, the 3- and 8-methyl analogues, showed improved selectivity (47- and 60-fold in a clonogenic assay). These two compounds also showed the highest "in vitro therapeutic indices" of the series as hypoxic cell radiosensitizers. Despite these favorable in vitro properties, neither compound had activity against hypoxic cells in SCCVII tumors when administered at 60% of the MTD.     

Radiosensitizers of hypoxic mammalian cells. 1-(Hydroxyaminoalkyl)-substituted nitroimidazoles

A series of novel 1-(hydroxyaminoalkyl)-substituted nitroimidazoles has been synthesized as potential radiosensitizers for hypoxic mammalian cells. These compounds were synthesized via N-(hydroxyalkyl)phthalimide nitroimidazole intermediates which, on reaction with hydrazine hydrate, yielded the corresponding amines. The intermediates were prepared by reacting the epoxide derived from nitroimidazole with phthalimide and/or the epoxide derived from phthalimide with the nitroimidazole. The method was used successfully for the preparation of 2-, 4- and 5-nitroimidazole derivatives. In a modification of this procedure, 1-(2-aminoethyl)-2-nitroimidazole has been prepared by a new route which avoids the use of aziridine. These agents were tested for cytotoxicity and radiosensitizing ability in vitro using Chinese hamster V79 cells. All of the 2-nitroimidazoles tested showed toxicity similar to that previously reported for misonidazole and Ro 03-8799 (1-(2-hydroxy-3-piperidinopropyl)-2-nitroimidazole), two compounds currently undergoing clinical evaluation. In addition, all the novel primary amines were shown to function as hypoxic cell radiosensitizers. The 2-nitroimidazole derivatives were the most efficient compounds to be examined and showed at least as much activity as misonidazole.     

Synthesis and evaluation of a series of 3,5-disubstituted benzisoxazole-4,7-diones. Potent radiosensitizers in vitro

A series of 3,5-disubstituted-2,1-benzisoxazole-4,7-diones was synthesized and evaluated as radiosensitizers both in vitro and in vivo. These compounds were designed as non-nitro electron-affinic agents in an effort to alleviate some of the toxicities seen with the 2-nitroimidazole radiosensitizers evaluated in the clinic. Several compounds in this series were potent radiosensitizers in vitro, with sensitizer enhancement ratios of 2.0-2.3 at concentrations less than 0.5 mM. Compounds with potent in vitro activity were also evaluated in vivo. However, none of these compounds showed radiosensitizing activity in vivo. The reduction potentials of these compounds were determined by cyclic voltammetry and compared to other electron-affinic radiosensitizers. In general, the reduction potentials of this series of compounds was slightly more positive than the 2-nitroimidazoles, but they fell within the range postulated as acceptable to yield in vivo activity. The results suggest that factors other than reduction potential may be responsible for the lack of in vivo radiosensitizing activity observed for this class of radiosensitizers.     

A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): the cycloalkylaziridines

A series of compounds related to alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069, 1) were synthesized and evaluated as selective hypoxic cell cytotoxic agents and as radiosensitizers. The aziridine moiety was replaced with a number of other potential alkylating groups including cycloalkylaziridines and azetidines. The data indicated that modification of the aziridine of 1 resulted in a substantial decrease in the ability of the compounds to selectively kill hypoxic cells. However, these modifications did not affect the compounds' in vitro radiosensitizing activity since many of the derivatives were as potent as 1. All of the compounds that were evaluated in vivo were less toxic than 1, and several members of this series had significant activity. The best compound was trans-alpha-[[(4-bromotetrahydro-2H-pyran-3-yl) amino]methyl]-2-nitro-1H-imidazole-1-ethanol (18), which, due to its activity and log P value, is a candidate for additional in vivo studies.     

Potential radiosensitizing agents. Dinitroimidazoles.

New compounds of the nitroimidazole series have been synthesized as radiosensitizers which selectively sensitize hypoxic cells to the lethal effect of radiation. The reaction of 2,4(5)-dinitroimidazole (2) with chloroethanol or hydrochloric acid yielded 4(5)-nitro-5(4)-chloroimidazole (3), which upon reaction with ethylene oxide yielded the 4-nitro-5-chloroimidazole-1-ethanol (6). Reaction of 2 with ethylene oxide resulted in a mixture of two compounds, the 2,4-dinitroimidazole-1-ethanol (4) and 2,3-dihydro-5-nitroimidazo[2,1-b]oxazole (5). The structure of the new heterocyclic compound 5 was confirmed by 1H NMR, mass spectrum, and X-ray crystallography. These agents were tested for their ability to sensitize hypoxic Escherichia coli cells to killing by ionizing radiation. Compound 4 was found to be the most active agent of this series of compounds.     

硝基(芳亚胺基)二乙基硫代硫酸钠和硝基苯丙氮酸衍生物的合成和放射增敏作用

A series of compounds was synthesized, these compounds were tested for Hela-S₃cells in vitro for radiosensitizing activity. Five of them are 2,2′- (arylimino)-diethyl-sodium thio-sulfate and two of them are phenylalanine derivatives. Most of them showed various degrees of ra-diosensitizing activity. Among them, SER of L07 was 1.89 at 3 mmol, and had low cytotoxicity toHela-S₃ cells;ID₅₀ was 18.8 mmol. The relationship between radiosensitizing effects and chemicalstructure was discussed. It offers a base for further exploration of selectively hypoxic cell radiosens-itizers.     

Synthesis and evaluation of novel electrophilic nitrofuran carboxamides and carboxylates as radiosensitizers and bioreductively activated cytotoxins

A series of 5-nitrofuran-2- and 3-carboxamides bearing alkylating side-chains has been synthesized and tested for their ability to radiosensitize selectively hypoxic Chinese hamster cells (V79) to the lethal effects of ionizing radiation and also for their ability to act directly and selectively as cytotoxic drugs on hypoxic V79 cells. The compounds were extremely efficient radiosensitizers of such cells in vitro and were more efficient than known nitroimidazoles of similar type. Their efficiencies as radiosensitizers correlated with their high electron affinity (E7(1] as measured by pulse-radiolysis. However the compounds showed little radiosensitizing activity towards KHT sarcomas in C3H mice. The compounds in this series of nitrofurans were generally more toxic towards hypoxic cells than towards oxic cells in vitro but were less effective upon the basis of a differential effect than were similar nitroimidazoles reported previously.     

Potential radiosensitizing agents. 7. 4(5)-Iodo-5(4)-nitroimidazole derivatives

A series of 4(5)-iodo-5(4)-nitro-1-substituted-imidazoles has been synthesized and tested for their ability to selectively radiosensitize hypoxic Chinese hamster cells (V-79) to the lethal effect of radiation. The reaction of 4(5)-iodo-5-(4)-nitroimidazole with 1,2-epoxy-3-methoxypropane and ethyl alpha-chloroacetate produced two isomeric products in each case, which were identified by their NMR spectra. The ethyl esters were further reacted with 3-picolylamine to produce corresponding amides. The 5-iodo-4-nitroimidazole-1-N-(3-picolyl)acetamide on further reaction with m-chloroperbenzoic acid produced the corresponding N-oxide. These compounds were generally more toxic to V-79 cells than the 2-nitroimidazole derivatives and were found to be more effective radiosensitizers in vitro. The 5-iodo-4-nitroimidazole derivatives were more efficient as sensitizers than the 4-iodo-5-nitroimidazole derivatives, and the sensitizing efficiency of this class of agents was found to have significant correlation with their partition coefficients.     

卟啉硝基咪唑类衍生物的合成及放射增敏作用

目的设计合成卟啉硝基咪唑类化合物,评价其体外肿瘤放射增敏活性,寻找新的肿瘤放射增敏剂。方法以吡咯、苯甲醛、硝基咪唑为原料,经环合、溴代、取代、络合等反应合成卟啉硝基咪唑类化合物及其金属配合物。采用MTT法考查该系列衍生物对人宫颈癌Helo细胞株的放射增敏活性。结果合成了12个未见文献报道的新化合物,其结构经紫外光谱、ESI质谱、红外光谱和核磁共振氢谱确证。在4Gy照射剂量下,化合物15、16、18、19对人宫颈癌Helo细胞株显示出很好的放射增敏活性,对肿瘤细胞的抑制率达到95%左右。结论金属卟啉结构单元的引入,极大地提高了硝基咪唑类的放射增敏活性。