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。     

L-异谷氨酰胺类氨肽酶N抑制剂的合成及初步活性

目的 设计并合成一系列新型L-异谷氨酰胺类衍生物,并测定其对氨肽酶N (APN)的抑制活性。方法 以L-谷氨酸为基本骨架,与3,4-二氯苯甲酸形成酰氯发生酰化、环合反应得到关键中间体环状酸酐,再经氨解反应合成目标化合物。采用体外抑酶试验测定化合物抑制氨肽酶N的活性。 结果与结论 合成了15个未见报道的L-异谷氨酰胺衍生物,其结构经过¹H-NMR、MS、和IR的确证。其中化合物I₄、I₆显示出较好的抑制氨肽酶N活性(IC₅₀=20~40 μmol.L^-1),有进一步研究的价值。     

肉桂酰天冬氨酸类氨肽酶N抑制剂的合成和初步活性研究

目的 以氨肽酶N（APN／CD13）为药物作用靶点,设计合成一系列新型的肉桂酰天冬氨酸类衍生物,并对其进行抑制活性评价。方法 以肉桂酸和L-天冬氨酸甲酯为基本原料经缩合、水解、酸化、环合反应得到关键中间体环状酸酐,再经氨解反应合成了一系列新型的肉桂酰天冬氨酸类衍生物;采用体外抑酶试验测定化合物对氨肽酶N的抑制活性。 结果与结论 合成了24个未见文献报道的肉桂酰天冬氨酸类衍生物, 其结构经过1H-NMR、MS谱确证。其中化合物6d,6g,6k, 6l显示出较好的抑制氨肽酶N活性(IC50=12~28 μmol.L-1),有进一步研究的价值。     

6-取代二氢哒嗪酮类化合物的合成及血小板聚集抑制作用

In order to develop more potent and less toxic, antithrombotic agents, ten 6-(4-substituted piperazinyl acetyl aminophenyi)-4, 5-dihydro-3(2H)-pyridazinones were synthesized. The title compounds were tested in vitro for platelet aggregation inhibitory activity with ADP-induced rat platelets and PAF-induced rabbit platelets. Preliminary tests showed that all of the pyridazinones could inhibit ADP-induced rat platelet aggregation. Ⅰ₇, Ⅰ₈, Ⅰ₉ were more potent than the control compound CI 930. Ⅰ₉ was the most potent compound with IC₅₀ of 0.99 μmol/L. Pertaining to PAF-induced rabbit platelet aggregation. Ⅰ₉ was the most potent inhibitor with IC₅₀ of 3.7 μmol/L.     

小分子拟肽类氨肽酶N抑制剂的合成及初步活性

目的设计合成小分子拟肽类衍生物并测定其抑制氨肽酶N（APN）的活性,研究它与酶的相互作用关系。方法通过模拟APN水解底物的过渡态,以D-丙氨酸为原料,经缩合反应合成小分子拟肽类衍生物;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12个未见文献报道的小分子拟肽类APN抑制剂,结构经红外光谱、核磁共振氢谱及质谱确证。结论目标化合物对APN有中等程度的抑制活性,可作为先导化合物开展进一步研究。     

6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及血小板聚集抑制作用

为了寻找理想的血小板聚集抑制剂，设计合成了１４个６－（４－取代苯基）－４，５－二氢－３（２Ｈ）－哒嗪酮类化合物．ＡＤＰ诱导，家兔体外血小板聚集实验表明，均有不同程度的抑制作用，其中化合物（Ⅰ８）的作用最强．     

6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集的作用

为了寻找较理想的抗血栓药物,本文设计合成了6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物16个。对ADP诱导的大鼠体外血小板聚集,均有不同程度的抑制作用。其中,化合物Ⅱ_2,Ⅱ3和Ⅱ_4的作用大于CCI-17810,又以Ⅱ_4的作用为最强。     

6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集的作用

为了寻找较理想的抗血栓药物,本文设计合成了6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物16个。对ADP诱导的大鼠体外血小板聚集,均有不同程度的抑制作用。其中,化合物Ⅱ₂,Ⅱ3和Ⅱ₄的作用大于CCI-17810,又以Ⅱ₄的作用为最强。     

N,N′-二异丙基碳二亚胺的合成

本文以工业异丙胺、二硫化碳为原料,通过加热回流脱除一分子的硫化氢,合成N,N′-二异丙基硫脲,收率94.8%;再以氯代乙二胺为氧化剂,氧化脱除另一分子的硫化氢,制备了N,N′-二异丙基碳二亚胺,收率92%。同时,还进行了氯代乙二胺的回收制备研究,使乙二胺在试验中循环使用,降低了成本。     

取代哌啶基苯骈咪唑啉酮类衍生物的合成及镇痛作用

本文报道取代哌啶基苯骈咪唑啉酮类衍生物的合成及镇痛活性。这类衍生物一般都具有吗啡样的镇痛作用(小鼠,ip,热板法),其中化合物1-{1-[1-(对甲苯基)乙基]-4-哌啶基}-3-(2-氰乙基)-2-苯骈咪唑啉酮(I_h)的镇痛强度为吗啡的500多倍。哌啶环的3位引入甲基后,镇痛作用明显下降。     

Design, synthesis, and preliminary activity evaluation of novel peptidomimetics as aminopeptidase N/CD13 inhibitors

The synthesis of a series of novel N-α-galloylated isoglutamic acid γ-amide peptidomimetics is described. Their enzymatic inhibition against aminopeptidase N (APN/CD13) and matrix metalloproteinase-2 (MMP-2) was tested. The preliminary activity assay revealed that most of the compounds displayed selective inhibition against APN as compared with MMP-2, with IC(50) values in a micromolar range. Within this series, compound 4 (IC(50) = 10.2 ± 0.9 μM) demonstrated comparable APN inhibition as compared with the positive control bestatin (IC(50) = 13.1 ± 0.7 μM), which might be a promising lead for further molecular optimizations.     

Progress in the development of aminopeptidase N (APN/CD13) inhibitors

Aminopeptidase N (APN; CD13) is a member of zinc-containing ectoenzymes family involved in the degradation of neutral or basic amino acids (Ala>Phe>Leu>Gly) from N-terminal of bioactive peptides and amide or arylamide derivatives of amino acids. The expression of APN being up regulated has been implicated in the pathogenesis of a variety of diseases such as cancer, leukemia, diabetic nephropathy, and rheumatoid arthritis. Thus, APN inhibitors (APNIs) are expected to be useful for the treatment of these disorders. This article reviews briefly the structure characteristic and possible function of APN. The proposed biomolecular structures and mechanism of action used in the design of APNIs are thoroughly covered. Major emphasis is on recently published potent, small molecular weight APNIs and their essential structure activity relationship (SAR). Finally, available clinical results of compounds in development are summarized in this review.     

N,N-双取代脲类克鲁斯氏锥体虫半胱氨酸蛋白酶小分子抑制剂的合成及其活性研究

目的寻找克鲁斯氏锥体虫体半胱氨酸蛋白酶Cruzain的小分子抑制剂.方法根据时Cruzain分子结构的计算机模拟设计结果,选用N,N-双取代脲为先导结构,目标化合物的合成采用Curtius重排反应,测定了化合物的体外抑制Cruzain的IC50值.结果设计并合成了21个未见文献报道的双取代脲衍生物,确证了它们的化学结构.结论生物活性测定结果显示,所合成的化合物均有不同程度的抑制Cruzain的活性,其中化合物Ⅳ9和Ⅳ17的活性好于对照药tf-175.Ⅳ8的活性与对照药tf-175相当.     

Recent advance in aminopeptidase N (APN/CD13) inhibitor research

APN is an important zinc dependent metallo-exopeptidase, which can degrade the extracellular matrix, and plays an important role in tumor invasion, metastasis and angiogenesis. it has been considered as a suitable target for anti-cancer drug design. Recently, research of structure-based APN inhibitors is becoming an interesting field, and many APN inhibitors have been reported. Here we review a series of APN inhibitors and the recent progress in this field.     

金刚烷胺衍生物的设计、合成及其抗禽流感病毒活性

目的 设计合成金刚烷胺衍生物并对其进行抗禽流感病毒活性测试。方法 以金刚烷甲酰氯和氨基酸甲酯盐酸盐为起始原料经酰胺化、水解、成盐等反应依次得到3个系列金刚烷胺衍生物。以金刚烷胺为阳性对照,采用幼犬肾（MDCK）细胞系噬斑形成实验测定目标化合物的抗禽流感病毒活性。结果与结论 共合成了20 个未见报道的新化合物,目标化合物的结构均经¹H-NMR、IR、MS 谱确证;仅有化合物 A₅ 显示出较好的抗禽流感病毒活性。     

Design,synthesis and activity evaluation of novel pyridinone derivatives as anti-HIV-1 dual (RT/IN) inhibitors

Three series of novel anti-immunodeficiency virus 1 (HIV-1) dual (RT/IN) inhibitors were rationally designed by introducing a functioning diketo acid (DKA) into pyridin-2-one scaffold. To efficiently analyze inhibitory activity, these compounds were screened against HIV-1 RT and IN respectively via surface plasmon resonance (SPR), and active compounds were subsequently evaluated by enzyme assay. It was noteworthy that compound A2 exhibited moderate activity against both HIV-1 RT and IN. This result provided information for further development of pyridinone analogues as potent dual HIV-1 inhibitors.     

茚酮氨基甲酸酯衍生物的设计合成及其对乙酰胆碱酯酶抑制活性的研究

目的设计合成茚酮氨基甲酸酯衍生物并进行乙酰胆碱酯酶(AChE)抑制活性测试。方法以羟基苯丙酸为起始原料,经分子内Friedel-Crafts酰化、羟基的氨基甲酸酯化和羟醛缩合3步反应合成目标物;采用Ellman法,以拉多替吉(ladostigil)为阳性对照,测试目标化合物对AChE的抑制活性。结果合成了8个未见文献报道的新化合物,其结构和纯度均经1H-NMR、MS谱测定。结论目标化合物对AChE均表现出一定的抑制活性,可作为先导化合物做进一步的改造和修饰。