抗血吸虫病药物的研究 取代(4-氨基-1-萘偶氮)苯和取代[4-(二乙氨基乙基氨基)-1-萘偶氮]苯类的合成

应用Elslager等法合成了35个取代(4-氨基-1-萘偶氮)苯和取代[4-(二乙氨基乙基氨基)-1-萘偶氮]苯类,同时又合成了5-(4-氨基-1-萘偶氮)尿嘧啶和5-[4-(二乙氨基乙基氨基)-1-萘偶氮]尿嘧啶。经动物筛选证明,有13个化合物对日本血吸虫病有预防和治疗作用,其中以2-氯-4-硝基[4-(二乙氨基乙基氨基)-1-萘偶氮]苯(化合物26)和5-[4-(二乙氨基乙基氨基)-1-萘偶氮]尿嘧啶(I_b)的治疗作用最显著,灭虫率达70％左右。     

3-二烃氨基甲基-6-取代基-苯并氧六圜-4-酮衍生物的制备

1.应用Mannich 反应制备了3-二烃氧甲基-6-硝基—,或6-乙酰氨基-或6-二甲氨基-苯并氧六圜-4-酮衍生物六种.2.Wiley 报导6-硝基-苯并氧六圜-4-酮进行Mannich 反应未能成功,我们应用三种方法制备成功.3.制备了6-氨基-或6-乙酰氨基—或6-二甲氨基-苯并氧六圜-4-酮并改进6-硝基-苯并氧六圜-4-酮的制备方法.     

抗血吸虫病药物的研究 取代(4-氨基-1-萘偶氮)苯和取代[4-(二乙氨基乙基氨基)-1-萘偶氮]苯类的合成

应用Elslager等法合成了35个取代(4-氨基-1-萘偶氮)苯和取代[4-(二乙氨基乙基氨基)-1-萘偶氮]苯类,同时又合成了5-(4-氨基-1-萘偶氮)尿嘧啶和5-[4-(二乙氨基乙基氨基)-1-萘偶氮]尿嘧啶。经动物筛选证明,有13个化合物对日本血吸虫病有预防和治疗作用,其中以2-氯-4-硝基[4-(二乙氨基乙基氨基)-1-萘偶氮]苯(化合物26)和5-[4-(二乙氨基乙基氨基)-1-萘偶氮]尿嘧啶(I_b)的治疗作用最显著,灭虫率达70%左右。     

4-硝基二苯醚-4′-硫代氨基甲酰胺类化合物的合成及其抗日本血吸虫作用

我们在改造硝硫氰胺(Ⅰ)的结构、寻找高效低毒的抗日本血吸虫病药物时,发现某些4-硝基二苯胺-4′-硫代氨基甲酸的衍生物,例如芳酯(Ⅱ)具有较强的抗日本血吸虫作用,其中4-硝基二苯胺-4′-氨基硫代甲酸(O)苯酯(硝硫苯酯,Phenithionate)的疗效与I相同,但毒性明显降低,已作为治疗日本血吸虫病新药,在临床试用。鉴于4-硝基-4′     

6-甲氧基-4-二烃氨基乙氨基喹啉衍生物的合成

合成了四种新的6-甲氧基-4-二烴氨基乙氨基喹啉衍生物,以供对感染日本血吸虫病实驗动物疗效試驗之用。     

硝硫苯酯及其有关硫代氨基甲酸衍生物的合成和抗日本血吸虫作用

本文报道22个4-硝基二苯胺-4′-硫代氨基甲酸衍生物和其二苯醚二苯硫醚类似物的合成,大多数化合物为氨基甲(?)酸芳酯。筛选结果表明4-硝基二苯胺-4′-氨基甲(?)酸芳酯和二苯醚类似物有较强的抗日本血吸虫作用而二苯硫醚类似物则无明显的抗虫作用。4-硝基二苯胺-4′-氨基甲(?)酸苯酯——硝硫苯酯(代号7720)已作为抗日本血吸虫病药物在临床试用,证明其疗效较高,毒性较低。本文还简要讨论了结构和抗日本血吸虫作用的关系。     

α,ω-双-(5-氨基苯骈二唑-2-巯)-烷及α,ω-(2-氨基-1,3,4-噻二唑-5-巯)-异丙醇及烷类化合物的合成

α,ω-双-(对-氨基苯氧基)-烷类化合物对动物感染的日本血吸虫有作用,但毒性太大。本文用苯骈二唑环及1,3,4-噻二唑环代替苯环,并以硫原子代替氧原子,共合成六个化合物,以观察化学结构和疗效的关系。以上化合物[除1,4-双-(5-氨基苯骈二唑-2-巯)-丁烷盐酸盐尚待试验外经动物试验,均无疗效。     

α,ω-双-(5-氨基苯骈二唑-2-巯)-烷及α,ω-(2-氨基-1,3,4-噻二唑-5-巯)-异丙醇及烷类化合物的合成

α,ω-双-(对-氨基苯氧基)-烷类化合物对动物感染的日本血吸虫有作用,但毒性太大。本文用苯骈二唑环及1,3,4-噻二唑环代替苯环,并以硫原子代替氧原子,共合成六个化合物,以观察化学结构和疗效的关系。以上化合物[除1,4-双-(5-氨基苯骈二唑-2-巯)-丁烷盐酸盐尚待试验外经动物试验,均无疗效。     

α,ω-双(对烃氧基苯氨基)-烷及 N,N′-双(对取代基苯基)-烃二醯胺类化合物的合成

据Raison和Standen等的报告,α,ω-双(对烴氨基苯氧基)-烷类化合物(Ⅰ)对于实驗动物感染的三种血吸虫病,都有較高疗效,但这类化合物毒性较大,尤以对视神經有严重的損害.我們改变其化学結构,合成了α,ω-双(对烴氧基苯氨基)-烷类(Ⅱ)及N,N′-双(对取代基苯基)-烴二醯胺(Ⅲ)及烴二酯(Ⅳ)类化合物十四种,以比較化学結构对于疗效和毒性的关系。     

十年来国外血吸虫病药物化学研究进展(一)

近十年来,血吸虫病药物化学研究工作大部分是以往课题的继续,例如:(一)硫蒽酮(米拉西尔)类;(二)4-氨基甲苯(米拉生)类;(三)四氢喹啉类;(四)三苯甲烷玫瑰苯胺及副玫瑰苯胺类;(五)有机磷化合物类等。在这几类中,值得介绍的有:(1)硫蒽酮(Lucan-thone)的有效代谢产物羟蒽酮(Hycanth-one)的发现;(2)苯并噻喃并吲唑类化合物;     

Pughiinin A,a sesquiterpene from the fungus Kionochaeta pughii BCC 3878

A novel secondary metabolite, pughiinin A, together with pycnidione, mevalonolactone, and 7-hydroxy-2-methylchromanone, was isolated from the seed fungus Kionochaeta pughii BCC 3878. The chemical structure was established by spectroscopic methods and by single crystal X-ray crystallography. Pughiinin A and pycnidione exhibited in vitro antiplasmodial activity against Plasmodium falciparum (K1 strain). Pycnidione also showed anti-cancer activity against KB and BC cell lines with the IC 50 values of 2.0 and 1.6 microg/mL, respectively.     

Substituierte 5-Deazaflavine, 4. Mitt. Synthese Donator-substituierter 5-Deazaalloxazine

Substituted 5-Deazaflavins, IV¹: Synthesis of Donor Substituted 5-Deazaalloxazines Treatment of the donor-substituted 6-anilinouracils 6 with Vilsmeier reagent results in three reactions depending on substitution: a) Donors in m-position cause regiospecific cyclisations yielding the 8-substituted 5-deazaalloxazines 8 . b) Donors in p-position yield the 5-formylanilinouracils 11 . c) With the strong m-dimethylamino donor additional formylation and in situ cyclisation to the 6-dimethylamino-9-formyl-5-deazaalloxazines 9 competes with the formation of 8 . These reactions are explained by postulating the vinylogous amidine 7 as intermediate.     

Synthese und komplexierende Eigenschaften symmetrischer N,N′-Tetra-(8-hydroxychinolyl-5-methyl)-α,ω-diaminoalkane

Synthesis and Complexing Properties of N,N,N′,N′-Tetrakis-(8-hydroxy-5-quinolylmethyl)-α,ω-diaminoalkanes A simple synthesis of N,N,N′,N′-tetrakis-(8-hydroxy-5-quinolylmethyl)-α,ω-diaminoalkanes, starting from 5-chloromethyl-8-hydroxyquinoline (basic material), and the complexing properties of these compounds are described.     

Synergistic enhancement of the acoustic startle reflex by dopamine D1 and 5-HT1A agonists and corresponding changes in c-Fos expression in the dorsal raphe of rats

Rationale: Although there is evidence that central opioid receptors are involved in immunomodulation, it has been only recently that an endogenous agonist, designated endomorphin-1, possessing high selectivity and affinity for the mu opioid receptor has been identified. Objective: The present study assesses the immunomodulatory effects of endomorphin-1 in the rat and provides further evaluation of the antinociceptive effects of endomorphin-1. Methods: Rats were surgically implanted with cannulae directed at the lateral cerebral ventricle. Animals received vehicle or endomorphin-1 at doses of 31.63 or 56.23 μg (ICV) and were tested for antinociception in two different assays, the warm water tail withdrawal procedure and the hotplate assay. Additional studies assessed the effect of naltrexone on the antinociception produced by endomorphin-1 in both antinociceptive assessments. Assessments of immune status following endomorphin-1 treatment included measurements of splenic natural killer cell activity, production of interferon-γ, and lymphocyte proliferative responses to mitogenic stimulation by Con-A, LPS, and the microbial superantigen, TSST-1. Results: Endomorphin-1 induced significant and naltrexone reversible antinociception 30 and 60 min following drug administration, as measured by the hotplate assay and warm water tail withdrawal procedure. In marked contrast, endomorphin-1 did not produce immunomodulatory effects up to 120 min following ICV administration. Conclusions: Endomorphin-1 produces antinociception but does not induce immunomodulatory effects in the rat. These findings suggest that it is possible to develop therapeutic strategies for separating antinociception and immunomodulatory properties through the mu opioid receptor. Electronic Publication     

4-Hydroxy-5-hydroxyimino-7-methyl-5H-pyrano (2,3-b) pyridine 8-oxide (author's transl)

4-Hydroxy-5-hydroxyimino-7-methyl-5H-pyrano[2,3-b]pyridine 8-Oxide In the course of studies on the reaction between dehydroacetic acid ( 1 ), N,N-dimethylformamide dimethyl acetal and hydroxylamine, a new two-step synthesis of a pyranopyridine with the structure of a vinylogous hydroxamic acid was discovered. The isomeric structures 5a - 8b , derived from the empirical formula C₉H₈N₂O₄ are discussed. The existence of 5a in solution is indicated by the spectral data (ms, ir, nmr).     

Synthesis and pp60c‐Src Tyrosine Kinase Inhibitory Activities of Novel Indole‐3‐Imine and Amine Derivatives Substituted at N1 and C5

A series of novel 1,3,5‐trisubstituted indole derivatives, namely, N‐benzyl 5‐phenyl indole‐3‐imine, N‐benzyl‐5‐(p‐fluorophenyl)indole‐3‐imine and their corresponding amine congeners, were designed and synthesized as pp60^c‐Src tyrosine kinase inhibitors, and their inhibitory activities toward pp60^c‐Src tyrosine kinase were evaluated by in‐vitro kinase assay. Pre‐screening at two doses of compounds against kinase target revealed that, except for the N‐benzyl‐5‐phenyl indole imine derivatives 7a – 7d , all indole derivatives show the target inhibition at varying levels. Consequently, the compounds, 8c , 8f , 8g , and 8h , were selected for prescreening tests. The dose‐response curves for up to six concentrations (250 to 7.8 μM) of the active compounds were obtained by tyrosine kinase assay and the four‐parameter logistic analysis of these data resulted in the IC₅₀s of 4.69, 74.79, 75.06, and 84.23 μM for compounds 8c , 8f , 8g , and 8h , respectively. Therefore, compound 8c , 1‐(1‐benzyl‐5‐phenyl‐1H‐indole‐3‐yl)‐N‐(4‐fluorobenzyl)methanamine·HCl, was the promising inhibitor for pp60^c‐Src, followed by compounds 8g and 8h . Under the same conditions, compound 8f did not provide any reasonable inhibition pattern to be considered as active compound. Therefore, among all four active compounds, compound 8f was not found suitable for further analysis.     

Protoberberine aus Reissert-Verbindungen, 2. Mitt.: Eine neue Synthese von 8-Methyldibenzo[a,g]chinolizidinen

Protoberberines from Reissert Compounds, II: A New Synthesis of 8-Methyldibenzo[a,g]quinolizidines The Reissert compounds 16 are benzylated by 2-bromomethylacetophenone dioxolane 14 to give the dihydroisoquinolines 5 . Treatment of 5 with KOH yields the 1-benzylisoquinolines 6 which spontaneously form the deoxygenated coralynes 4 in acidic solution. 4a and 18 are reduced by NaBH₄ to give the 8-methyl-trans-dibenzoquinolizidines 19 . The sequence 5 → 6 → 4 → 19 is a new efficient access to coralyne analogues and 8-substituted tetrahydroprotoberberines.- Bromination of 2-methylacetophenone does not lead to 2-bromomethylacetophenone but to the benzalbromide 9 or to the phenacylbromide 11 .     

阿司匹林对鼻咽癌CNE-1、5-8F细胞增殖、迁移与侵袭作用机制研究

目的 探讨阿司匹林对人鼻咽癌CNE-1、5-8F细胞增殖、迁移与侵袭的影响和机制。方法 将人鼻咽癌CNE-1、5-8F细胞株分为对照组和阿司匹林（0.00、1.25、2.50、5.00、10.00mmol/L）处理组。噻唑蓝（MTT）法检测不同浓度阿司匹林作用24、48、72h后对CNE-1、5-8F细胞的增殖能力,以半数抑制浓度（IC₅₀）作为后续实验药物处理浓度。集落形成实验检测CNE-1和5-8F细胞增殖能力,Transwell实验检测CNE-1和5-8F细胞迁移及侵袭能力的变化,Western blotting法检测CNE-1和5-8F细胞中蛋白激酶B（Akt）、磷脂酰肌醇3-激酶（PI3K）、波形蛋白（Vimentin）、E-钙黏蛋白（E-cadherin）、Snail蛋白相对表达水平。结果 人鼻咽癌CNE-1、5-8F细胞分别经1.25、2.50、5.00、10.00mmol/L阿司匹林处理后,细胞增殖均受到不同程度抑制,且呈时间及浓度相关性,IC₅₀分别为3.3、2.7mmol/L。与对照组相比,经阿司匹林处理后,鼻咽癌CNE-1、5-8F细胞的细胞增殖和集落形成能力明显下降（P＜0.01）。与对照组相比,经阿司匹林处理后,划痕愈合率显著降低（P＜0.05）。Trasnwell迁移实验结果表明,与对照组相比,阿司匹林处理组鼻咽癌细胞CNE-1和5-8F 48h穿过小室的数目显著减少（P＜0.05、0.001）。与对照组相比,阿司匹林处理组CNE-1、5-8F细胞的E-cadherin蛋白表达显著增加（P＜0.05）,PI3K、Akt、Vimentin、Snail蛋白表达显著下降（P＜0.05、0.01）。结论 阿司匹林可通过上调E-cadherin蛋白的表达、抑制上皮间质转化进程从而抑制人鼻咽癌CNE-1、5-8F细胞迁移侵袭,同时下调PI3K、Akt、Vimentin、Snail蛋白的表达进而抑制CNE-1、5-8F细胞增殖、迁移和侵袭能力。     

Synthesis of 2-(3-Substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]octanes and 2α-(3-Substituted-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-enes as Potential Muscarinic Agonists

Radioligand binding affinities of seven muscarinic receptor ligands which possess an oxadiazole ring side chain have been determined in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations to determine the selectivity for subtypes of muscarinic receptor. The ratios of binding constants in brain membranes were measured as an indicator of potential agonist activity against [³H]QNB and [³H]Oxo-M. These muscarinic ligands did not discriminate the subtypes of muscarinic receptors. Six muscarinic ligands which have a 3-amino- or 3-methyl-1,2,4-oxadiazol-5-yl groups attached to the 8-methyl-8-azabicyclo[3.2.1]oct-2-ene or 8-methyl-8-azabicyclo[3.2.1]octane head group show binding constants between 2.04 x 10^–6 and 1.79 x 10^–5 M in rat heart, rat brain, and m₁- or m₃-transfected CHO cell membrane preparations. 1-Methyl-2-[3-amino-1,2,4-oxadiazol-5-yl]piperidine shows low binding constants of approximately 10^–4 M in rat heart and rat brain. (1R,5S)-2-[3-Amino-1,2,4-oxadiazol-5-yl]-8-methyl-8-azabicyclo-[3.2.1]oct-2-ene [(1R,5S)-17] was the most active compound.     

Differential coupling of 5-HT1A receptors occupied by 5-HT or 8-OH-DPAT to adenylyl cyclase

Summary Human serotonin (5-hydroxytryptamine, 5-HT)-1A receptors have been transfected in NIH-3T3 cells, and their coupling to adenylyl cyclase was analysed depending on (1) the number of receptor expressed, (2) the experimental conditions used, (3) the nature of the agonists. Two monoclonal cell lines were used, expressing low (45 fmol/mg) and high (500 fmol/mg) levels of 5-HT_1A receptor. Two methods were tested to study the negative coupling of the transfected 5-HT_1A receptors to adenylyl cyclase: (1) measurement of CAMP production in intact cells, (2) measurement of adenylyl cyclase activity in vitro on membrane preparations. Studies on intact cells revealed that an increase in the receptor concentration was followed by (1) an increase in the efficacies of 5-HT, 5-CT (5-carboxamidotryptamine) and 8-hydroxy2-(di-n-propylamino)tetralin (8-OH-DPAT), (2) a 2 to 3-fold increase in the potency of 5-CT and 8-OH-DPAT, but no change in the potency of 5-HT. In membrane preparations, 8-OH-DPAT dose-response curve was shifted leftwards when the receptor concentration became higher whereas the corresponding shift was smaller for 5-HT and absent for 5-CT. Surprisingly, on membrane preparations, 8-OH-DPAT was a partial agonist relative to 5-HT. The relative efficacy of 8-OH-DPAT was lower in the clone expressing the lowest level of receptor. This partial agonist behavior of 8-OH-DPAT could be modulated by the ionic conditions under which the adenylyl cyclase activity was measured. When physiological intracellular concentrations of Na⁺, Mg²⁺ and K⁺ were used, 8-OH-DPAT became an almost full agonist relative to 5-HT.These data indicate that (1) the classical pharmacological models do not exactly fit with characteristics of the negative coupling between transfected 5-HT_1A receptors and adenylyl cyclase; (2) on membranes, the experimental procedures (ionic conditions) can modify this coupling differently depending on the nature of the agonist.Abbreviations 5-HT 5-hydroxytryptamine (serotonin) - 8-OHDPAT 8-hydroxy-2-(di-n-propylamino)-tetraline - 5-CT 5-carboxamidotryptamine - IBMX isobutyl methyl xanthine - BSA bovine serum albumine - EC₅₀ half maximal efficacy - DXM dexamethasone - PTX Bordetella pertussis toxin - G protein GTP-binding protein Correspondence to A. Varrault at the above address