N-(4-取代氨基-4-氧代丁酰基)-N-取代甘氨酸的合成

血管紧张素转化酶抑制剂(ACEI)是近年发展的一类新型抗高血压和治疗心力衰竭的有效药物。有关研究工作还在世界范围内广泛进行。 本研究组前曾报道一类具有降压活性的N-取代甘氨酸的合成。作者等根据Cushman等的血管紧张素转化酶(ACE)与底物的作用模型和构效关系,在保持3个主要作用部分(即ACE     

N-(4-甲氧羰基-4-邻苯二甲酰亚氨基丁酰基)-N-取代甘氨酸、脯氨酸和焦谷氨酸的合成

报道11个预期有血管紧张素转化酶抑制活性的N-(4-甲氧羰基-4-邻苯二甲酰亚氨基丁酰基)-N-取代甘氨酸(VII_1～9)、脯氨酸(VII₁₀)和焦谷氨酸(VIl₁₁)的合成和鉴定。所有上述化合物以及与VⅡ_1～9相应的叔丁酯(VI_1～9)均未见文献报道。药理初试结果显示，化合物VII₈，VII₉和VI₁₀均有明显降压活性。     

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(XI_1～4)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(XII_1～5)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(X_1～9)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。     

O-对甲脒苯氧烷基-N-取代酪氨酸甲酯的合成与抗血小板聚集活性

非肽类纤维蛋白原受体拮抗剂阻止血小板聚集的最后一步,即活化的血小板与纤维蛋白原之间的结合[1,2],是一类有新作用机制的抗血栓剂,为80年代末,90年代初以来国际上抗血栓药物研究的热点。通过对纤维蛋白原及ＲＧＤ肽的结构模拟,已获得一些高效化合物,且克服了肽类化合物的某些缺点,成为这类药物的研究方向[3]。前文[4,5]报道了Ｏ对甲脒苯胺基羰甲基及Ｏ对甲脒苯氧乙基Ｎ取代酪氨酸甲酯类化合物的合成及其抗血小板活性,已出现了一些有意义的苗头。为了进一步考察空间臂的极性和长度对化合物活性的影响,本文合成了一系列新的化合物ＩＶａ～ｉ…     

含L-4-氧代赖氨酸和N3-(4-甲氧基富马酰)-L-2,3-二氨基丙酸寡肽类似物的合成及其抗白念珠菌活性

运用“违法传递”概念,根据白念珠菌对寡肽的传送特点,设计并合成了8个含L-4-氧代赖氨酸(以下称I-677)和N³-(4-甲氧基富马酰)-L-2,3-二氨基丙酸(以下称FMDP)的寡肽类似物,均系新化合物。体外抗白念珠菌试验表明:I-677-FMDP-肽(I-677-FMDP,I-677-AA-FMDP,其中AA=Nva,Val,Leu,Phe,Pro,D,L-p-Cl- Phe,D-Pgly)是I-677单体摩尔活性的40～770倍,是FMDP的60～1130倍,其摩尔最低抑菌浓度为6.56×10^-9～3.5×10^-10mol·disk^-1。羧肽酶A存在时化合物I-677-FMDP体外抗菌试验表明,含FMDP的化合物I-677-FMDP能抵抗羧肽酶A的酶解。     

4-S-(5-酰氨基-1,3,4-噻二唑-2-基)-4-脱氧-4′-去甲基表鬼臼毒素衍生物的合成与抗肿瘤活性

基于在4′-去甲基表鬼臼毒素母核C₄位上联结含有杂原子的芳香环取代基,以此考察其结构与活性关系的设想,设计并合成了10个标题化合物。体外L₁₂₁₀白血病细胞与KB细胞生长抑制试验结果表明,这类化合物有较强的抗肿瘤活性。其中化合物SIPI-92-1772,1774,1775,1776,1777与1779的活性超过临床用药依托泊甙。其余化合物活性与依托泊甙相当或略低。     

血吸虫病化学治疗的研究——ⅩⅩⅩⅣ.α-氯-β-(5-硝基-2-呋喃)丙烯酰胺类及其乙烯噁二唑类衍生物的合成

Synthesis of 35 new compounds of α-chloro-β-(5-nitro-2-furyl) acrylamides and 5-[α-chloro-β-(5-nitro-2-furyl ) vinyl]-oxadiazoles by known methods are reported. In preliminary test in mice 10 compounds were found to possess pronounced activity against Schistosomiasis japonica. Among these Ⅰ₁₂, Ⅰ₁₃, Ⅰ₁₄, Ⅰ₂₀, Ⅱ₁ and Ⅱ₈ were shown to be the most effective.     

血吸虫病化学治疗的研究——Ⅳ.β-(5-硝基-2-呋喃)丙酰胺类及其α,β-二溴取代衍生物的合成

本文报道38个β-(5-硝基-2-呋喃)丙酰胺及其α,β-二溴取代衍生物的合成。这类化合物的制备是以相应的β-(5-硝基-2-呋喃)丙烯酰胺类化合物(Ⅰ)进行催化氢化或与溴加成而得。经动物筛选发现β-(5-硝基-2-呋喃)丙烯酰胺类的丙烯双键以氢饱和以后生成丙酰胺类化合物(Ⅱ),对感染日本血吸虫病的小白鼠完全失去治疗或预防作用。而以溴饱和双键的α,β-二溴化合物(Ⅲ)则仍然有较显著的杀虫作用。其中尤以β-(5-硝基-2-呋喃)-α,β-二溴丙酰异丙胺(Ⅲ₁₁)和β-(5-硝基-2-呋喃)-α,β-二溴丙酰甘氨酸乙酯(Ⅲ₂₄)最为显著,后者曾试用于临床,证明有一定疗效。     

S-(2-18F-氟代乙基)-L-蛋氨酸的合成及其放射药理活性

目的研制肿瘤氨基酸代谢显像剂S-(2-18F-氟代乙基)-L-蛋氨酸(18FEMET),评价其区分炎症和肿瘤的价值。方法采用亲核取代反应,由两步法合成18FEMET。测定正常小鼠、肿瘤及炎症小鼠体内FEMET生物分布,对模型小鼠进行18FEMET PET显像,并与2-18F-2-脱氧-D-葡萄糖(FDG)和O-(2-18F-氟代乙基)-L-酪氨酸(FET)比较。结果18FEMET手工合成时间约为70 min,未校正总放化产率为15%～25%,放化纯度大于95%。正常小鼠中胰腺、肾脏、结肠、肝和心脏等脏器摄取18FEMET较高,且放射性滞留时间较长,血液和脑摄取18FEMET较低。肿瘤细胞可高度摄取18FEMET,FDG和FET,炎症组织也可高度摄取FDG,但几乎不摄取18FEMET和FET。结论18FEMET制备简便,能够区分肿瘤和炎症,可望成为一种有前景的特异性肿瘤氨基酸代谢PET显像剂。     

双(2,6-哌嗪二酮)类抗肿瘤药物的研究:2,3-二乙酰氧基-1,4-二(3′,5′-二酮-N4′-取代哌嗪甲基)苯的合成

Seventeen compounds having the structure of 2,3-diacetoxy-1,4-bis(3′,5′- dioxo-N⁴′-substituted piperazinyl methyl)benzene were designed and synthesized based on chelation hypothesis. Their antitumor activities on P388 cells,Hep cells and SGC 7901 cells in vitro were tested. Preliminary results showed that compound 4e has potent antitumor effect against P388 cells and.Hep cells in vitro.     

Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents

The 5-hydroxytryptamine 5-HT_1A receptor has been the focus of considerable research effort for over a decade. However, the definitive classification of this receptor and the full characterization of its pharmacology have awaited the development of highly selective 5-HT_1A receptor antagonists. The only compounds available until recently have been either nonselective or partial 5-HT_1A receptor agonists (or a combination of both). Confusion has arisen owing to the use of different pharmacological models in examining the functional activity of 5-HT_1A receptor ligands. Several partial agonists display only antagonist activity in models of postsynaptic 5-HT_1A receptor function, whereas their agonist properties are revealed in models of presynaptic, somatodendritic 5-HT_1A autoreceptor function. In view of these considerations, the term ‘silent antagonist’ has been introduced to distinguish true 5-HT_1A receptor antagonists from partial agonists. Allan Fletcher and colleagues review the pharmacological properties of the first selective silent 5-HT_1A receptor antagonists that have been recently discovered and discuss the potential therapeutic utility of these novel compounds.     

选择性保护合成2-〔4(S)-4-酰氨基-3-氧代-2-异噁唑烷基〕-5-氧代-2-四氢呋喃甲酸类化合物及其体外抑菌活性

采用两种新选择性保护方法由L-丝氨酸和α-酮戊二酸为原料经几步合成了8个目标化合物。体外抑菌该验表明除TMV外,对金葡球菌209P和大肠杆菌44822具有中等到强的活性。     

1,4-二［3-(氨基硫代甲酰硫基)丙酰基］哌嗪类化合物的合成及其抗肿瘤活性

目的　寻找并合成低毒、有较强抗肿瘤活性的哌嗪类化合物。方法和结果　以1,4-二(3-溴丙酰基)哌嗪为先导物,合成了一系列1,4-二［3-(氨基硫代甲酰硫基)丙酰基］哌嗪类新化合物,并测试了这些化合物(4a-j)对8种瘤细胞株的体外抗肿瘤活性。结论　体外抗肿瘤活性试验结果表明,大多数化合物显示一定的抗肿瘤活性,尤其是化合物4c,4d和4e,浓度在10μmol.L^-1时,对HL-60细胞抑制率分别为44%,90%和70%。     

3-芳基/芳氧甲基-6-芳基-1,2,4-三唑并［3,4-b］-1,3,4-噻二唑衍生物的合成及生物活性

噻二唑类杂环化合物有广泛的生物活性,如消炎、驱虫、除草、调节植物生长、防止水稻白叶枯病、柑桔溃疡病、蕃茄青枯病等［１～３］。而１,２,４三唑类杂环化合物也有相当广泛的生物活性,如抗菌、抗痉挛、消炎、抗血小板凝聚及调节植物生长等［４～６］。如果合成既...     

2-〔4(s)-4-酚胺基-3-氧代-2-异噁唑烷基〕-5-氧代-2-四氢呋喃甲酸钠类化合物的合成

以L-丝氨酸和α-酮戊二酸为原料,采用三条合成路线,经6～8步反应,合成8个目标化合物。其部份中间体的结构经IR,PMR,MS及元素分析证实。产物的结构也经IR及PMR证实。体外抑菌试验表明,TM7和TM8显示较强的广谱抑菌活性,TM6则具有中等强度。TM2和TM3对金葡菌也有一定活性。     

2,4-二氨基-6-(取代苄基)-5-甲基吡啶[2,3-d]并嘧啶衍生物的合成及抗癌活性的研究

二氨基吡啶并嘧啶类化合物具有很强的抑制二氢叶酸还原酶的作用。这类化合物中BW301u已进行临床试验以治疗癌症。本文报道了17个2,4-二氨基-6-取代苄基-5-甲基-吡啶[2,3-d]并嘧啶类化合物的合成及对L_(1210)细胞的抑制作用。合成化合物的结构经由MS-EI,~1H-NMR及元素分析确证。以MTT法测定了它们对L_(1210)细胞的抑制作用。     

疟疾防治药物的研究——Ⅹ.2,4-二氨基-6-N1,N2-二取代肼基-喹唑啉类衍生物的合成及其抗疟作用

本文报道了2,4-二氨基-6-N¹,N²-二取代肼基-喹唑啉类衍生物的合成及其抗疟活性的研究。这类化合物的合成是以2,4-二氨基6-取代苄基氨基-喹唑啉为原料经亚硝化、还原成为2,4-二氨基6-(N¹-取代苄基)—肼基喹唑啉,再与相应的醛缩合而成。此类化合物经伯氏鼠疟原虫抑制性治疗初筛表明有少数具有一定的效果。有11个化合物经约氏鼠疟原虫—斯氏按蚊系统病因性初筛有效。其中化合物Ⅱ_1,7,8,11,15和Ⅲ₁口服2.5mg/kg,连续3天,可使受试小鼠全部得到保护。     

Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors

In animals given citalopram (10 mg/kg) twice daily for 14 days a further dose of 1 mg/kg, administered 24 h after the last dose, markedly increased cortical dialysate serotonin (5-hydroxytryptamine, 5-HT), but had no effect in control animals. The effect on dialysate 5-HT in the dorsal raphe was not increased by the chronic treatment. At 25 μg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin, an agonist at 5-HT_1A receptors, reduced cortical 5-HT output in controls but not in animals treated chronically with citalopram whereas 50 μg/kg reduced 5-HT output in both groups. These findings suggest that somatodendritic 5-HT_1A receptors are desentisized after chronic treatment with citalopram and this results in facilitation of its effect on cortical dialysate 5-HT. These results also agree with the concept that the effect of 5-HT re-uptake inhibitors on increasing 5-HT output in the frontal cortex is attenuated by their simultaneous ability to activate somatodendritic 5-HT_1A receptors via an increase of endogenous 5-HT in the raphe region.     

Selective destruction of the serotonergic fibers of the fornix-fimbria and cingulum bundle increases 5-HT1 but not 5-HT2 receptors in rat midbrain

Selected and localized lesions of serotonergic (5-HT) neurons were made by microinjection of 5,7-dihydroxytryptamine (5,7-DHT), after pretreatment with desipramine, into the cingulum bundle and fornix-fimbria; these are the major serotonergic hippocampal inputs from the median raphe nucleus. Two weeks after the lesion, the binding of [³H]5-HT (5-HT₁ receptor) was determined in the hippocampus which receives the afferent terminals and, in addition, in the septum/hypothalamus and midbrain from where the fibers originate. Scatchard analysis showed there was no significant change in binding parameters in the hippocampus; however, a significant increase was observed in the B_max in the midbrain (38%) with no change in the K_D. The caudate which receives 5-HT inputs via other 5-HT tracts was not affected by the lesion. The changes in 5-HT₁ receptor number or affinity were not observed 6 days or 5 weeks after the lesion. The binding of the ligands [³H]spiroperidol and [³H]ketanserin to the 5-HT₂ receptor population was also determined in the same brain areas; no changes in receptor binding occurred two weeks after the lesion. These experiments demonstrate that a selective lesion of the serotonergic system can increase 5-HT₁ receptors in the midbrain, which contains the serotonin cell bodies. In addition, as 5-HT₂ binding is not altered, this further supports the hypothesis that 5-HT₁ and 5-HT₂ receptors are distinct populations of receptors.     

1-烷基-1-苄基-4-(3-氯-2-羟基)丙基哌嗪季铵盐的合成及生物活性

设计合成了7个1-烷基-1-苄基-4-(3-氯-2-羟基)丙基哌嗪季铵盐(Ia～g)。生物活性试验结果表明,苄基苯环上连有强吸电子取代基时,可使抗炎和镇痛活性明显增强;季铵盐中的负离子对生物活性有一定的影响。在20mg·kg^-1的剂量下,Id和Ie的抗炎活性和Ie的镇痛活性明显。