DL型丁胱亚磺酰亚胺对大鼠C_6神经胶质瘤细胞放射增敏效应研究

目的　研究有氧及乏氧状态下DL型丁胱亚磺酰亚胺(DL BSO)对大鼠C6神经胶质瘤细胞的放射增敏效应。方法　以60 Coγ射线为放射源 ,分有氧和乏氧状态下单纯照射组、加药照射组。采用细胞克隆形成方法观察DL BSO对神经胶质瘤细胞的放射增敏效应。结果　有氧状态下 ,DL BSO的放射增敏作用和药物作用时间有关。 0 1mmol·L-1DL BSO用药 2、6、12h ,未能观察到放射增敏作用 ,放射增敏作用仅在用药后 2 4、4 8h出现。乏氧状态下 ,0 1mmol·L-1DL BSO用药后 ,各时间点 (2～ 4 8h)均可见放射增敏效应。有氧、乏氧状态下不同浓度DL BSO的放射增敏作用和药物浓度有关。结论　DL BSO对有氧及乏氧状态下的大鼠C6神经胶质瘤细胞均有放射增敏作用。离体状态下 ,DL BSO主要表现出乏氧增敏作用 ,并呈现一定的时间、浓度依赖关系。     

吡啶丙烯酰氨基酸衍生物的设计、合成及其对离体HeLa-S_3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。     

大黄素型羟基蒽醌类化合物对宫颈癌HeLa细胞放射敏感性的影响

目的:研究大黄中活性成分大黄素型羟基蒽醌类化合物对宫颈癌HeLa细胞的生长抑制和体外放射增敏活性。方法:MTT法测定大黄素型羟基蒽醌类化合物对宫颈癌HeLa细胞的生长抑制活性,集落形成实验测定各化合物对HeLa细胞的放射增敏活性,单靶多击模型拟合剂量存活曲线,计算放射生物学参数和放射增敏比。结果:大黄素、大黄酸、芦荟大黄素、大黄酚对宫颈癌HeLa细胞的抑制作用呈剂量依赖性,其半数抑制浓度(IC50)值分别为262.1、79.9、59.6、435.6μmol·L-1;集落形成实验结果显示,给药合并照射组细胞存活分数低于单纯照射组,芦荟大黄素、大黄酸对宫颈癌HeLa细胞体外放射增敏比分别为1.84和1.13。结论:芦荟大黄素等羟基蒽醌类化合物对宫颈癌HeLa细胞具有较为明显的生长抑制活性,并且对宫颈癌HeLa细胞具有放射增敏活性。     

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。     

马蔺子甲素对碳离子放射增敏作用

目的　探讨马蔺子甲素（ Ｑ） 对碳离子的放射增敏作用并与γ射线进行比较。方法　在有氧和乏氧条件下,荷瘤小鼠被随机分为６ 组：对照组;碳离子与γ射线治疗组;碳离子与γ射线加药治疗组;单独用药组。以动脉夹阻断小鼠局部血流以造成肿瘤乏氧２０ ｍｉｎ ,比较在有氧与无氧情况下的增敏作用。结果　此药对乏氧肿瘤的增敏比（ｓｅｎｓｉｔｉｚａｔｉｏｎｅｎｈａｎｃｅｍｅｎｔ ｒａｔｉｏ , Ｓ Ｅ Ｒ） 值明显大于不乏氧肿瘤,且６ Ｇｙ 碳离子的放射增敏作用大于１８ Ｇｙ γ射线的放射增敏作用。结论　马蔺子甲素对小鼠正常皮肤无增敏作用,对小鼠肿瘤乏氧细胞具有选择性地放射增敏的作用     

2，6-二取代-1，4-苯醌类化合物的合成及其体外放射增敏作用

马蔺子甲素是一种２,６－二取代苯醌类化合物,具有明显的乏氧细胞放射增敏作用。通过对马蔺子甲素的化学结构进行修饰,合成了１２个２,６－二取代苯醌类化合物,初步药理实验结果显示：它们具有较高的放射增敏作用,但是乏氧选择性细胞毒作用较低。     

放射增敏剂的研究进展

过去的20年间,乏氧细胞放射增敏剂的研究一直引起人们相当大的兴趣,它的发展将有助于解决肿瘤乏氧细胞对射线的抗性而致肿瘤放疗治愈率低的难题,也可以用于化疗增敏。已发现一些类型化合物有放射增敏作用,但是研究较多、最有希望发展成为临床使用药物的目前有三类,即硝基杂环类,有机-N-氧化物类和醌类。一、硝基杂环类 20年前发现硝基杂环类具有选择性乏氧细胞增敏作用。最初对对硝基苯乙酮类化合物的研究表明,对乏氧细胞的增敏活性为硝基芳环类化合物所特有。其后,对多种硝     

肿瘤乏氧放射增敏剂的研究进展

摘 要 改善肿瘤细胞的乏氧,可有效减少其对放疗的抵抗,从而提高治愈率。目前用于改善肿瘤细胞缺氧减少放射抵抗的化合物已经不仅仅局限于原有的亲电性放射增敏剂,许多具有靶向性的乏氧放射增敏剂也成为研究重点。本文在介绍肿瘤乏氧机制的基础上,对新型靶向制剂、亲电性乏氧细胞放射增敏剂、生物还原剂与植物天然提取物这四类乏氧细胞放射增敏剂的研究进展进行了综述。     

瑞波特Ruibote

[通用名]雷贝拉唑,Rabeprazole. [化学名称]2-[[[4-(3-甲氧基丙氧基)-3-甲基-a-吡啶基]甲基]亚硫酰基]-1H-苯并咪唑钠,其结构式为:     

Aminopyridine carbamic acid esters: synthesis and potential as acetylcholinesterase inhibitors and acetylcholine releasers.

4-Amino-3-pyridyl carbamates (2a-c) were synthesized as potential acetylcholinesterase inhibitors and acetylcholine releasers on the basis of the reported activity of the analogous N-(4-amino-3-pyridyl)-N',N'-dimethylurea (1). Although 4-amino-3-pyridyl N,N-dimethylcarbamate (2b) showed good cholinesterase inhibition [concentration that elicited a 50% reduction in the maximal enzyme response (IC50) was 13.4 microM], it had no effect on the stimulated release of [3H]acetylcholine from rat striatal slices. 4-[[(Dimethylamino)methylene]amino]-3-pyridyl N,N-dimethylcarbamate (7a), an intermediate in the synthesis of 2b, demonstrated surprisingly good cholinesterase inhibition (IC50 was 9.4 microM) but showed no activity as a release. A precursor to 7a, N-(3-hydroxy-4-pyridyl)-N',N'-dimethylformamidine (6a), showed some activity in release but was not an esterase inhibitor, whereas the precursor to 6a, 4-amino-3-pyridinol (5a), was a potent releaser. A new synthesis of 5a, based on an ortho-directed lithiation strategy, is also reported.     

泰利霉素侧链的合成

3-溴乙酰基吡啶经氨解、甲酰化、环合反应制得4-(3-吡啶基)-1H-咪唑,进而与N-(4-溴丁基)邻苯二甲酰亚胺缩合后肼解,制得泰利霉素侧链化合物4-[4-(3-吡啶基)-1H-咪唑-1-基]-1-丁胺,总收率为33%.     

Analysis for N2-(pyridyloxobutyl)deoxyguanosine adducts in DNA of tissues exposed to tritium-labeled 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine

The tobacco-specific carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are metabolically activated to DNA binding intermediates, partially via 4-(3-pyridyl)-4-oxobutanediazohydroxide (7) or related carbonium ions. Previous studies have shown that generation of 7 from 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone (11) in the presence of deoxyguanosine yields a major adduct identified as 2'-deoxy-N-[1-methyl-3-oxo-3-(3-pyridyl)propyl]guanosine (adduct 1). These results suggested that adduct 1 should be present in DNA of tissues that can metabolically activate NNK and NNN. In the present study, we evaluate the formation of adduct 1 and its structurally related straight-chain analogue 2'-deoxy-N-[4-oxo-4-(3-pyridyl)butyl]guanosine (adduct 2) in DNA of tissues of rats treated with [5-3H]NNK or [5-3H]NNN, and in DNA of nasal mucosa that had been cultured in medium containing [5-3H]NNK or [5-3H]NNN. Hepatic DNA from rats treated with [5-3H]NNK was enzymatically hydrolyzed to deoxyribonucleosides and analyzed by HPLC. One of the radioactive peaks, peak E, coeluted with adduct 1. However, treatment of peak E with NaBH4 resulted in the formation of products different from those produced by NaBH4 treatment of adduct 1, demonstrating that adduct 1 could not be detected under these conditions. Hydrolysis of peak E with acid produced 4-hydroxy-1-(3-pyridyl)-1-butanone (9), suggesting that peak E might be adduct 2. Therefore, adduct 2 was synthesized by reaction of deoxyguanosine with 1-(3-pyridyl)butane-1,4-dione (5) in the presence of NaCNBH3.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and antiulcer activity of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo [1,5-a]pyrimidine-7-ones

A series of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo-[1,5-a]pyrimidine-7-ones were synthesized and evaluated for the inhibition of stress-induced gastric ulcers in the rat after oral administration. Several molecules were found to be very active. The particularly interesting compound (E)-1-(3-chlorophenyl)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo[1,5-a]- pyrimidine-7-one was chosen for wider pharmacological investigation.     

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.     

Synthesis of carbon-11 labeled iodinated cocaine derivatives and their distribution in baboon brain measured using positron emission tomography.

Three iodine-substituted derivatives of cocaine, methyl esters of 3-[(2'-, 3'-, and 4'-iodobenzoyl)oxy]-8-methyl-[1R-(exo,exo)]-8- azabicyclo[3.2.1]octane-2 carboxylic acid (2a-c), were synthesized and subjected to N-demethylation to give the corresponding noriodococaines 3-[(2'-,3'-, and 4'-iodobenzoyl)oxy]-[1R-(exo,exo)]-8- azabicyclo[3.2.1]-octane-2-carboxylic acid (3a-c). These were remethylated with [11C]CH3I to give the [N-11C-methyl]iodococaines 4a-c which were examined in baboon brain in vivo using positron emission tomography (PET). Compared to [N-11C]cocaine itself the regional distributions were changed from a highly specific localization in the corpus striatum to more diffuse patterns which included the cerebellum and cortex. Peak brain uptakes and clearance kinetics were also changed. [N-11C]-o-Iodococaine (4a) had a peak uptake in the striatum at 4-5 min after injection of only 17% that of cocaine in the same animal. The peak uptake of [N-11C]-p-iodococaine (4c) was 60% of that of [N-11C]cocaine and a clearance half-time of approximately 55 min, twice that of [N-11C]cocaine. [N-11C]-m-Iodococaine (4b) displayed half the uptake of [N-11C]cocaine, buts its clearance was similar to that of the parent molecule. The fractions of unmetabolized tracer in blood plasma at 1-30 min were higher for 4a-c than for [N-11C]cocaine. Plasma protein binding experiments showed 10%, 0.3%, 1.6%, and 6% as the free fraction for cocaine and o-, m-, and p-iodococaines respectively, consistent with the low brain uptake observed for the ortho isomer, and implicated alpha 1-acid glycoprotein as responsible for the low free fraction of o-iodococaine. The potencies of 2a-c to displace tritiated cocaine from striatal membranes were p-iodo approximately cocaine greater than m-iodo approximately o-iodo.     

硝基呋喃腙类结构和抗血吸虫作用关系的初步探讨

本文根据硝基呋喃腙对小白鼠血吸虫病具有預防作用的发現,合成了数十种同型和同烯系物,进行了化学結构与抗血吸虫作用关系的初步探討。发現5-硝基呋喃-2-甲醛縮硫氨脲、5-硝基呋喃-2-丙烯醛縮氨脲和縮硫氨脲以及β-(5-硝基呋喃-2-)-丙烯酰-(4-甲基)-(口派)嗶嗪、(4-苄基)-(口派)嗶嗪、(4-二乙氨基甲酰)-(口派)嗶嗪、甲胺和乙烯亚胺等8种化合物对小白鼠体內血吸虫童虫具有抑制生长的作用,后两种还兼具对成虫的治疗作用。     

Synthesis, physicochemical and anticonvulsant properties of new N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione. Part II

A series of N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane- (1a-e), 2-azaspiro[4.5]decane- (2a-e) and 6-methyl-2-azaspiro[4.5]decane-1,3-dione (3a-e) were synthesized and tested for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. To explain the possible mechanism of action, the most active compounds N-(3-methylpyridine-2-yl)-2-azaspiro[4.4]nonane-1,3-dione (1b), N-(3-methylpyridine-2-yl)-2-azaspiro[4.5]decane-1,3-dione (2b), N-(4-methylpyridine-2-yl)-2-azaspiro[4.5]decane-1,3-dione (2c), and N-(3-methylpyridine-2-yl)-6-methyl-2-azaspiro[4.5]decane-1,3-dione (3b) were tested in vitro for their influence on voltage-sensitive calcium channel receptors, however, they revealed low affinities. For all synthesized compounds the lipophilicity was determined by use of RP-TLC method. The correlation between the lipophilicity and anticonvulsant activity was obtained--the higher the lipophilicity the stronger the anticonvulsant efficacy.     

Evaluation of WO2012032067 and WO2012055846: two selective PI3Kδ inhibitors, which is GSK-2269557?

Two applications each claim crystalline forms, salts and compositions of a single selective PI3Kδ inhibitor. The subject of both applications are specific, previously disclosed, 6-aryl-4-(5-aminomethyloxazol-2-yl)indazole derivatives, respectively N-[5-[4-[5-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]oxazol-2-yl]-1H-indazol-6-yl]-2-methoxy-3-pyridyl]methanesulfonamide and 2-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-5-[(4-isopropylpiperazin-1-yl)methyl]oxazole.     

Diuretika, 3. Mitt. 1-Carbocyclisch und heterocyclisch substituierte 4-Aminopyrazolo[3,4-d]pyrimidine

Diuretics, III: 4-Aminopyrazolo[3,4-d]pyrimidines with Carbocyclic or Heterocyclic Substituents at N-1 As analogues of the diuretically active 4,6-diamino-1-(2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidine, the 4-aminopyrazolo[3,4-d]pyrimidines 3a–g were prepared by condensation of the 5-amino-4-cyanopyrazoles 1a–g with formamide (2) .