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。     

2—硝基咪唑类乏氧细胞放射线增敏剂的合成及其抑制血管增生作用

设计并合成了２－氯代乙酰氨甲酰基－１（２－硝基咪唑基）－３－叔丁氧基丙烷,２－溴代乙酰氨甲酰基－１－（２－硝基咪唑基）－３－（４－叔丁基）酚基丙烷及结构类似的光学异构体,测定了卤代乙酰氨甲酰基－２－硝基咪唑类化合物体外乏氧细胞放射增敏活性和体内抑制血管增生活性。结果表明：２－硝基咪唑侧链上引入卤代乙酰氨甲酰基可明显增大体外乏氧细胞放射增敏活性,而且表现出较强的体内抑制血管增生活性。     

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。     

硝基咪唑类抗肿瘤放射增敏剂研究进展

硝基咪唑类放射增敏剂是目前国内外研究较为成熟并具有发展前景的一类抗肿瘤放射增敏药。对几类具有代表性的硝基咪唑类化合物的化学结构、生物学活性、作用机制进行综述。     

有机锗倍半氧化物类化合物的合成

目的:为寻找新型低毒有效放射增敏剂,合成了3 种类型有机锗倍半氧化物。方法:取代桂皮酸或取代苯丙炔酸与三氯锗仿反应,所得加成物经水解即得锗倍半氧化物;三氯锗基丙酰氯与亮氨酸乙酯或苯丙氨酸乙酯反应,所得产物水解即得N-(β-倍半氧锗基 丙酰) 氨基酸酯。结果:合成的8个化合物中,7个(2 ～8) 为新化合物,羧基-β-( 取代苯基)乙烯基锗倍半氧化物为新类型化合物。结论:离体和整体实验结果表明,化合物4 有较显著的放射增敏作用,为新型低毒有效放射增敏剂。     

辐射化学修饰剂沙纳唑研究进展

沙纳唑是硝基三氮唑类乏氧细胞辐射化学修饰剂,其不良反应小、放射增敏作用强。本文综述其药动学特点、免疫调节作用、放射增敏作用、化学增敏作用、及其在临床肿瘤治疗中的研究结果。     

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。     

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

乏氧细胞对射线所具有的较大抗性是对某些人类肿瘤进行放疗失效的主要原因。放射增敏剂的研究目的是为了提高射线在正常组织可耐受剂量下对肿瘤细胞的杀伤率,从而提高放疗效果。目前试用于临床的放射增散剂misoniizole(MISO)是一种硝基咪唑类化合物,由于其较强的神经毒性,限制了这种药物的推广和使用。为寻找新的低毒有效的放射增敏剂,我们设计并合成了一系列化合物,试验了它们对离体Hela-S_3细胞的放射增敏作用。     

放射增敏剂的研究进展

目的:为放射增敏剂的研发提供参考。方法:根据文献,综述了非乏氧细胞选择性增敏剂与乏氧细胞选择性增敏剂的研究现状。结果与结论:非乏氧细胞选择性增敏剂以抗肿瘤药物为主,增敏效果好但毒性较大;乏氧细胞选择性增敏剂以经典增敏剂的衍生物为主,其增敏作用目前没有可靠的临床数据支持,仍需进一步的结构改造。对于已有增敏活性的药物进行结构改造,以及新靶点、新机制的研究将成为未来放射增敏剂的研究热点。     

N－（1－乙氧羰基－3－苯氨甲酰基丙基）甘氨酰甘氨酸衍生物的合成

报道４个Ｎ－（１－［１－乙氧羰基－３－（对甲）苯氨甲酰基］丙基甘氨酰｝－Ｎ－取代甘氨酸（ＸＩ１～４）和５个１－［１－乙（或甲）氧羰基－３－（对甲）苯氨甲酰基］丙基－４－取代－１，４－哌嗪－２，５－二酮（ＸＩＩ１～５）共９个估计有血管紧张素转化酶抑制活性化合物的合成和鉴定。所有这些化合物及９个相应的酯（Ｘ１～９）均未见文献报道。药理初试结果，化合物ＸＩＩ２，ＸＩＩ５，ＸＩ４和ＸＩＩ１均有较强降压活性。     

Anti-HAV activity of some newly synthesized triazolo[4,3-b]pyridazines

6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazine-3(2H)-thione 2 was used as precursor for the preparation of some novel 3-S-substituted-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine derivatives 3-11. Furthermore, the preparation of 1-[2-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-acetyl]-1H-pyrazole derivative 13 and 5-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanylmethyl)-[1,3,4]oxadiazole derivatives 15 and 17, are described. Some of the prepared products revealed a promising antiviral activity against hepatitis-A virus (HAV, MBB-cell culture adapted strain). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with the test compounds. Compound 15 showed the highest effect on HAV compared to the other tested compounds.     

Antimycobacterial activity of substituted isosteres of pyridine- and pyrazinecarboxylic acids. 2

Pyridines and pyrazines substituted with 1,2,4-oxadiazole-5-ones, 1,2,4-oxadiazole-5-thiones, and 1,3,4-oxathiazoline-2-ones were synthesized and tested against Mycobacterium tuberculosis. The two former ring systems were documented in the literature to act as carboxylic acid isosteres. The latter series was synthesized as possible synthetic intermediates to 1,2,4-thiadiazole-3-ones and was included in this study due to their interesting activity. Pivaloyloxymethyl derivatives of the isosteres were also prepared in order to increase their lipophilicity and therefore improve their cellular permeability. The derivatized isosteres were expected to be biotransformed by esterases to the active species after penetration of the mycobacterial cell wall. Biological properties of the compounds were compared with the unmodified polar isosteres of pyrazinoic and nicotinic acids. The majority of the compounds exhibited activities ranging from 0.5 to 16 times the potency of pyrazinamide.     

Synthesis and biological evaluation of indole containing derivatives of thiosemicarbazide and their cyclic 1,2,4-triazole and 1,3,4-thiadiazole analogs

New indolic derivatives of thiosemicarbazides and some cyclic 1,2,4-triazol-5-thione analogs were synthesized. The newly synthesized compounds as well as some indole containing thiosemicarbazides, 1,2,4-triazoles and 1,3,4- thiadiazoles, which have been reported previously, were investigated for antimicrobial, antifungal and antiphage activity. Certain thiosemicarbazide derivatives and the corresponding cyclic 1,2,4-triazole analogs showed selective antimicrobial or antifungal activity, while they lack any antiphage activity. Antiphage activity was detected for one compound, bearing the 1,3,4-thiadiazole nucleus. The selectively active compounds cover a wide range of lipophilicity. Structure-activity relations show a remarkably similarity in the antimicrobial and antifungal behaviour of the thiosemicarbazides and their cyclic triazo-thien-5-yl analogs, while alpha-naphtyl substitution in the non indolic portion of the molecule is favorable. C5 substitution on the indolic nucleus may also be critical for selective activity.     

Quinoxaline derivatives. Part II: Synthesis and antimicrobial testing of 1,2,4-triazolo[4,3-a]quinoxalines, 1,2,4-triazino[4,3-a]quinoxalines and 2-pyrazolylquinoxalines

Three main classes of quinoxaline derivatives have been synthesized. The first class comprises the synthesis of three novel series of 1,2,4-triazolo[4,3-a]quinoxalines; namely 1-substituted-1,2,4-triazolo[4,3-a]quinoxalines 3a-f, 1-substituted aminomethyl-1,2,4-triazolo[4,3-a]quinoxalines 14a-d and 1-cyano or ethoxycarbonylmethyl-1,2,4-triazolo[4,3-a]quinoxalines 6, 12. The second class involves the synthesis of 2-substituted-1 H-1,2,4-triazino[4,3-a]quinoxalines 4a-d. The third class deals with the synthesis of a variety of 2-pyrazolylquinoxalines, namely 2-(5-amino-3-arylpyrazol-1-yl)-3-phenylquinoxalines 5a-d, 2-[5-hydroxy-3-phenyl-4-(4-substituted sulfamoylphenyl)azopyrazol-1-yl]-3-phenylquinoxalines 15a, b, and 2-(5-hydroxy-4-nitroso-3-phenylpyrazol-1-yl)-3-phenylquinoxalin e (16). The prepared compounds were tested in vitro for their antimicrobial activity. Compounds 13 and 14b exhibited promising antifungal activity against C. albicans (MIC 25, 50 mu/ml respectively). Compound 13 was as active as the antibiotic nystatin.     

Synthesis of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives of potential anti-inflammatory activity

A series of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives 4-10 were synthesized by rearrangement of 4-(3-pyridyl)-hydrazono-2-phenyl-2-oxazolin-5-one 3 in the presence of different nucleophiles to afford derivatives 4, 7, and 8, while hydroxamic acid derivative 6 was prepared from reaction of methyl ester 4 with hydroxylamine hydrochloride. Semicarbazide 9 and thiosemicarbazide 10, derivatives of the 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid, were synthesized via hydrazide 8 with potassium cyanate and appropriate isothiocyanate, respectively. The structures of the synthesized compounds were confirmed by elemental analyses, IR, (1)H-NMR, and mass spectra. The results of the anti-inflammatory activity of the synthesized derivatives showed that most of the tested compounds 4-10 showed significant inhibition against carrageenan-induced rat paw edema in albino rats. Derivatives 4 and 8 showed promising results and were found to be equipotent or more potent than Indomethacin and Celecoxib as reference drugs at two dose levels, 5 and 10 mg/kg, and they have no ulcerogenic activity.     

Synthesis of certain thiosemicarbazide and triazole derivatives as potential antimicrobial agents

Two novel series of thiosemicarbazide derivatives were synthesized: 2-[4-(substituted thiocarbamoylhydrazinocarbonyl) phenoxymethyl]-1H-benzimidazoles and 1-benzyl-2-[4-(substituted thiocarbamoylhydrazinocarbonyl) phenoxymethyl]-1H-benzimidazoles, and cyclised to 2-[4-(4-substituted-4H-1,2,4-triazole-5-thion-3-yl)phenoxymethy ]-1H-benzimidazoles and 1-benzyl-2-[4-(4-substituted-4H-1,2,4-triazole-5- 5-thion-3-yl)phenoxymethyl]-1H-benzimidazoles, respectively. The antimicrobial activity of the prepared compounds was tested.     

Synthesis of certain substituted quinoxalines as antimicrobial agents (part II)

Several fused triazolo and ditriazoloquinoxaline derivatives such as 1-aryl-4-chloro-[1,2,4]triazolo[4,3-a]quinoxalines (3a-d), 4-alkoxy[1,2,4]triazolo[4,3-a]quinoxalines (4a,b), 4-substituted-amino-[1,2,4] triazolo[4,3-a]quinoxalines (5a-h), 1-(aryl)-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-thione (6), 4-(arylidenehydrazino)1-phenyl-[1,2,4]triazolo[4,3-a]quinoxalines (10a-e) and [1,2,4]ditriazolo[4,3-a:3',4'-c]quinoxaline derivatives (11-13) have been synthesized and some of these derivatives were evaluated for antimicrobial and antifungal activity in vitro. It was found that compounds 3a and 9b possess potent antibacterial activity compared to the standard tetracycline.     

Synthesis, structure, and antiparasitic activity of sulfamoyl derivatives of ribavirin

The triazole nucleoside derivatives 1-(5'-O-sulfamoyl-beta-D-ribofuranosyl) [1,2,4]triazole-3-carboxamide (2), 1-(5'-O-sulfamoyl-beta-D-ribofuranosyl) [1,2,4]triazole-3-thiocarboxamide (3), and 1-(5'-O-sulfamoyl-beta-D-ribofuranosyl)-[1,2,4]triazole-3- carbonitrile (4) were synthesized. Suitably protected triazole nucleosides were converted to their corresponding 5'-sulfamoyl derivatives, which on subsequent deprotection gave the desired compounds in good yields. The structures of compounds 2-4 were confirmed by X-ray crystallographic analysis. All three compounds showed significant antiparasitic activity in vitro, while 2 showed significant activity in vivo against Leishmania donovani and Trypanosoma brucei.     

Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.

A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.