N,N′-亚烷基双(取代苯酚)氨基乙酸的合成及对放射性核素钍-234的促排效果

本文报道合成的16个N,N′-亚烷基双(取代苯酚)氨基乙酸除化合物3,4外对放射性钍-234的加速排出均有较好的效果。其中有二个化合物促排效果达到70%以上,根据动物实验结果初步探讨了构效关系。     

N′-取代苯基-2-苯并噻唑磺酰脲类化合物的合成

目的为寻找具有抗肿瘤活性的新化合物,设计合成一系列N′-取代苯基-2-苯并噻唑磺酰脲类化合物。方法以2-巯基苯并噻唑为原料,经弱氧化、氨化、再氧化得到2-苯并噻唑磺酰胺;各种取代苯胺与三光气反应制得一系列取代苯异氰酸酯;2-苯并噻唑磺酰胺与各种取代苯异氰酸酯反应,得到一系列N′-取代苯基-2-苯并噻唑磺酰脲类化合物。结果与结论合成了15个N＇-取代苯基-2-苯并噻唑磺酰脲类化合物,除化合物6b外其余14个未见文献报道。目标化合物的结构均经承、1H-NMR和MS确证。初步体外活性筛选结果表明,目标化合物6b、6e、6n有一定的抗肿瘤活性,进一步的抗肿瘤活性测试正在进行中。     

N,N′-双-(对-取代苯基)-α,ω-烷二胺类的制备

α,ω-双-[对-氨基苯氧基]-烷类化合物对感染日本血吸虫病实驗动物有作用,但毒性較高,经改变其結构,将氨基移至苯核內侧,对位用甲基,卤素或硝基替代,成N,N′-双-(对-取代苯基)-α,ω-烷二胺类化合物,以察其化学結构和疗效的关系。 N,N′-双-(对-取代苯基)-α,ω-烷二胺类化合物由对-甲苯磺酰对-取代苯胺,氫氧化鈉和α,ω-二溴烷类在乙醇中縮合成N,N′-双-(对-甲苯磺酰)-N,N′-双-(对-取代苯基)-α,ω-烷二胺,然后用氫溴酸和苯酚进行水解而得,其中溴代化合物水解时核上溴原子可能脫落,所以用盐酸水解之。此类化合物中N,N′-双-(对-氯苯基)-α,ω-庚二胺和N,N′-双-(对-溴苯基)-α,ω-庚二胺另由相应的对-取代苯胺和-α,ω-二溴烷类及碳酸氫鈉在乙醇中縮合制备。     

抗结核药物的研究—N,N′-双酰肼及多酰肼类化合物

一、N,N′-双酰肼类化合物的一般制法系将酸制成酯,酯与水合肼作用生成酰肼,酰肼与酰氯于无水吡啶或无水乙腈中反应,即可制得。本文合成酰肼化合物一个,N,N′-双酰肼类化合物共六个,其中三个化合物经药理试验结果,无抗结核作用。二、多酰肼类化合物系采用酯与水合肼作用而得,其氨硫脲的衍生物可采用酰氯与氨硫脲反应而得。本文合成多酰肼及其氨硫脲类衍生物共六个(两个系已知的),其中四个化合物经药理试验结果,无抗结核作用。     

N,N′-双-(对-取代苯基)-α,ω-烷二胺类的制备

α,ω-双-[对-氨基苯氧基]-烷类化合物对感染日本血吸虫病实驗动物有作用,但毒性較高,经改变其結构,将氨基移至苯核內侧,对位用甲基,卤素或硝基替代,成N,N′-双-(对-取代苯基)-α,ω-烷二胺类化合物,以察其化学結构和疗效的关系。N,N′-双-(对-取代苯基)-α,ω-烷二胺类化合物由对-甲苯磺酰对-取代苯胺,氫氧化鈉和α,ω-二溴烷类在乙醇中縮合成N,N′-双-(对-甲苯磺酰)-N,N′-双-(对-取代苯基)-α,ω-烷二胺,然后用氫溴酸和苯酚进行水解而得,其中溴代化合物水解时核上溴原子可能脫落,所以用盐酸水解之。此类化合物中N,N′-双-(对-氯苯基)-α,ω-庚二胺和N,N′-双-(对-溴苯基)-α,ω-庚二胺另由相应的对-取代苯胺和-α,ω-二溴烷类及碳酸氫鈉在乙醇中縮合制备。     

N,N’-二卤代苯基-4-甲氧基-1,3-苯二磺酰胺类化合物的设计、合成及体外抗血小板聚集活性评价

依据药物化学结构设计中拼合和等排原则,拼合抗血小板聚集药物吡考他胺(picotamide)和利曲他班(linotroban)的结构,用磺酰基代替甲酰基,设计合成了N,N’-二卤代苯基-4-甲氧基-1,3-苯二磺酰胺系列化合物(4a~4m、5a~5n),各化合物的结构由IR、1H NMR和HR-MS光谱确证。以吡考他胺为阳性对照药,采用Born比浊法检测目标化合物抗二磷酸腺苷(ADP)诱导的体外抗血小板聚集活性,结果显示其中12个化合物(4b、4f、4l、5b、5d~5g、5j、5k、5m和5n)对ADP诱导的血小板聚集的抑制活性优于阳性对照药吡考他胺。此外,初步探讨了目标化合物的构效关系。     

吡喃鎓衍生物N2的体外抗真菌活性研究

目的 研究N2系列化合物的抗真菌作用。方法 利用微量液基稀释法考察化合物N2系列化合物的体外抗真菌活性；在菌丝和被膜诱导条件下考察N2化合物对白念珠菌菌丝和被膜形成的抑制效果。结果 N2化合物对临床常见条件致病真菌白念珠菌有明显抗真菌活性；N2化合物可以明显抑制白念珠菌菌丝生长和被膜的形成；N2化合物可以通过损伤白念珠菌细胞膜和细胞壁发挥杀菌作用。结论 N2化合物具有较为广泛的抗真菌谱，能起到明显的体外抗真菌效果，对真菌菌丝和生物被膜的形成均有明显的抑制作用，可以认为N2化合物具有抗真菌潜力，可作为先导化合物，指导进一步改造。筛选获得了具有抗真菌活性的N2化合物，为抗真菌药物研发和解决真菌耐药问题提供新思路。     

以氨肽酶 N为靶点的N-取代-2，5-吡咯烷二酮类肽的设计合成及活性研究

目的 寻找具有氨肽酶N(APN,CD13)抑制活性的新型化合物并测定其抑制氨肽酶N的活性;考察目标化合物与APN活性位点的结合,研究目标化合物与酶的相互作用关系。方法 以光学纯的天冬酰胺为原料,经Boc保护、环合、酯化、脱Boc保护、酰化、氢化还原、羟肟酸化等反应合成目标化合物。借助FlexX对接软件,研究目标化合物与APN活性位点的结合情况;采用体外抑酶试验测定目标化合物抑制APN的活性。结果 合成了14个未见文献报道的 N-取代-2,5-吡咯烷二酮类肽类APN抑制剂,其结构经¹H-NMR、MS谱确证。结论 目标化合物均对APN/CD13具有一定的抑制活性,其中,化合物7h的活性较好,与计算机对接结果一致。     

O5',N6-双取代腺苷衍生物的合成及降血脂活性评价

目的 设计合成O5',N6-双取代腺苷衍生物,并评价其降血脂活性,寻找新型降血脂化合物.方法 以6-氯嘌呤为起始原料,经4步反应合成目标化合物;通过测试目标化合物对油酸刺激下HepG2细胞内三酰甘油水平的影响及高胆固醇血脂症小鼠总胆固醇含量的影响评价化合物的活性.结果 与结论合成了12个未见文献报道的新化合物,其结构经...     

4-甲氧基-N,N′-二(2-取代苯基)-1,3-苯二磺酰胺类化合物的合成及体外抗血小板聚集活性研究

目的 寻找新的抗血小板聚集药物并研究4-甲氧基-N,N′-二(2-取代苯基)- 1,3-苯二磺酰胺类化合物的不同2-位取代苯基对抗血小板聚集活性的影响。方法 以吡考他胺为先导化合物,用取代苯磺酰氨基代替3-吡啶甲氨基对先导化合物进行结构改造：以苯甲醚为原料,采用文献方法与氯磺酸反应直接制得重要中间体4-甲氧基-1,3-苯二磺酰氯;该中间体与2-取代苯胺类化合物经胺解反应制得目标化合物。以吡考他胺和阿司匹林为阳性对照药物,采用Born比浊法对目标化合物进行体外抗血小板聚集活性初筛。结果与结论 共制得12个化合物(4a~4l),其化学结构由IR、1H-NMR和MS光谱确证,其中9个化合物(4a~4c, 4e~4i和4l)未见文献报道。药理试验结果表明,5个化合物表现出较好的体外抗血小板聚集活性：化合物4g、4f和4b的活性优于吡考他胺和阿司匹林;化合物4i的活性略低于阿司匹林;化合物4h的活性与吡考他胺相当。     

3-甲基-5-硝基呋喃衍生物的合成

本文报道在硝基呋喃类药物的呋喃环3位上进行结构修饰。根据3位甲基有利于硝基与酶活性部位的巯基进行亲核取代,有可能提高其抗菌杀虫活性的设想,合成了3-甲基呋喃嘧酮和3-甲基呋喃丙胺等新化合物19个。与母体化合物进行抗菌杀虫活性的比较,以探索环上甲基所起的作用。这类化合物的合成是以丙酮为原料,经Claisen缩合、Darzen反应、McFadyen反应成为3-甲基呋喃甲醛,再经Knoevenagel反应、硝化、缩合成为化合物Ⅰ。3-甲基呋喃醛经肟化、硝化、缩合成为化合物Ⅱ。有关生物活性比较和理论探讨将另文发表。     

METHODS OF ASSESSING THE PERCUTANEOUS ABSORPTION OF VOLATILE CHEMICALS IN ISOLATED PERFUSED SKIN: STUDIES WITH CHLOROPENT AFLUOROBENZENE AND DICHLOROBENZENE

The experimental determination of dermal absorption of volatile chemicals is fraught with difficulties. The isolated perfused porcine skin flap (IPPSF) is a biologically intact, perfused skin preparation that has been employed to predict dermal absorption of chemicals in humans. The purpose of this work was to explore various experimental dosing strategies for volatile chemicals using dichlorobenzene (DCB) and chloropentafluorobenzene (CPFB) as model compounds. Effects of complete occlusion and various strategies of vapor trapping, vapor dosing, and solvent effects were explored. The results suggest that dosing methodology is a major determinant of dermal absorption and could easily skew results obtained from different systems. A biologically sensitive system such as the IPPSF is particularly sensitive to the manipulations required to ensure precise dosing of these compounds. An interesting finding was that the effects of solvents on compound absorption that are routinely described in liquid dosing scenarios were also detected when both the compound and solvent were exposed during the vapor phase.     

A STUDY IN MICE OF BROMO AND CHLORO ACYLUREA ANALOGUES OF THE SEDATIVE-HYPNOTIC BROMUREIDES

1. A series of 1-(2-chloroacyl)ureas, related to the sedative-hypnotic drugs brom-valetone and carbromal, was synthesized and tested in mice to determine central depressant and acute toxic effects. Four 1-(2-bromoacyl)ureas and two 3-halo compounds were included for comparison. 2. Large variations in potency were seen between the compounds. Much of this can be ascribed to differences in lipophilicity. Among homologous 1-(2-chloroacyl)ureas, those with 6 acyl carbons had maximal potency. Among groups of structural isomers, the most potent were 2-halo, 3-alkyl substituted compounds. 3. The most potent compounds were also those with the largest ratios of hypnotic to lethal activity. 4. The variation in the onset and duration of action of these compounds enables a choice to be made for a compound with a particular set of characteristics.     

苯并异硒唑酮磺酰胺类化合物的抗炎作用

目的　研究苯并异硒唑酮磺酰胺类化合物A和B抗炎作用。方法　Boyden 小室法测定中性粒细胞趋化;紫外分光光度法测定髓过氧化物酶活性;染色法测定肥大细胞脱颗粒。结果　化合物A和B均可抑制fMLPP诱导的兔外周血中性粒细胞趋化反应;外涂给药均可抑制巴豆油引起的小鼠髓过氧化物酶的升高。在10^-7～10^-5　mol.L^-1浓度下可抑制化合物48/80诱导的肥大细胞脱颗粒,并与浓度呈正相关。结论　苯并异硒唑酮磺酰胺类化合物A和B有明确的抗炎作用。     

N,N'-Bisbenzylidenebenzene-1,4-diamines and N,N'-Bisbenzylidenenaphthalene-1,4-diamines as Sirtuin Type 2 (SIRT2) Inhibitors

A series of N,N'-bisbenzylidenebenzene-1,4-diamine and N,N'-bisbenzylidenenaphthalene-1,4-diamine derivatives were synthesized as inhibitors for human sirtuin type 2 (SIRT2). The design of the new compounds was based on two earlier reported hits from molecular modeling and virtual screening. The most potent compound was N,N'-bis(2-hydroxybenzylidene)benzene-1,4-diamine, which was equipotent with the most potent hit compound and well-known SIRT2 inhibitor sirtinol.     

Anti-inflammatory activity of some potassium salts of N,N-disubstituted 4-aminoazobenzenesulfonic acids in rat adjuvant arthritis

Anti-inflammatory effects of three potassium salts of N,N-disubstituted 4-aminoazobenzenesulfonic acids were investigated and compared to that of acetylsalicylic acid (ASA) in rats with adjuvant arthritis (AA). Prophylactic oral administration of all compounds in a dose of 150 mg/kg ameliorated AA symptoms in animals. The most pronounced anti-inflammatory activity at the end of the experiment showed compound 1 containing imino group: it significantly suppressed joint swelling by 48.2% in female and by 44.2% in male rats with AA. The development of polyarthritis after the treatment with this compound was the lowest in female (20%) and male (40%) rats (in control--100% of animals with polyarthritis). All derivatives, and especially compound 1, also improved the systemic parameters of disease such as blood indices and internal organs' weight, and showed no toxicity on the main organs such as liver and spleen.     

Synthesis and antitubulin activity of N1- and N4-substituted 3,5-dinitro sulfanilamides against African trypanosomes and Leishmania

Thirty analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide (GB-II-5, compound 3), a new antikinetoplastid antimitotic agent, have been synthesized and evaluated. The addition of simple functional groups to the N1 aromatic ring generally decreases antiparasitic and antimitotic potency, but placement of a dibutyl substituent at the N4 nitrogen to give N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (compound 35) augments antitrypanosomal and antileishmanial activity. Compound 35 possesses IC(50) values of 0.12 and 2.6 microM against cultured T. brucei and L. donovani amastigote-like forms, surpassing the activity of compound 3 against these parasites by 3.4- and 1.9-fold, respectively. Compound 35 inhibits the assembly of leishmanial tubulin with an IC(50) of 6.9 microM and displays antimitotic effects in cultured T. brucei as assessed by flow cytometry, but shows little effect on purified mammalian tubulin, and displays 100-fold selectivity for trypanosomes over two mammalian cell lines. Although 3 and 35 were not effective in initial in vivo antitrypanosomal assays, the in vitro potency and selectivity of these compounds make N(1)-aryl-3,5-dinitro-N(4),N(4)-dialkylsulfanilamides a promising new class of antikinetoplastid agents that act on parasite tubulin.     

骨质疏松防治药物研究(3):喹啉酮类衍生物的合成及其抗骨质疏松活性

骨质疏松防治药物研究（３）：喹啉酮类衍生物的合成及其抗骨质疏松活性徐鸣夏，段文虎，郑虎（成都华西医科大学药化教研室６１００４１）雌激素可预防和治疗绝经后的骨质疏松症，其中雌二醇最常用。但长期使用雌激素有诱发乳腺癌及子宫内膜癌的危险，因此，需有既具抗骨...     

取代4-苯乙烯基香豆素的合成及其抗肿瘤活性

目的为寻找有抗肿瘤活性的物质,设计并合成了一系列取代4-苯乙烯基香豆素化合物。方法用相转移Wittig反应和Horner反应得目的物,用¹HNMR,MS和元素分析确证其结构;用HL-60,KB,HCT-8和Bel-7402进行体外细胞毒活性筛选。结果所合成的20个(1-20)4-苯乙烯基香豆素为新化合物。化合物18对KB细胞株有效。结论化合物18显示了抗肿瘤活性,值得进一步研究。