具有7-氮杂吲哚结构的化合物活性研究进展

含有7-氮杂吲哚结构的化合物在药学、功能材料等方面具有广泛的应用,该类化合物很多都具有抑制蛋白酶的活性,它们在抗多巴胺、抗组胺、抗炎、抗菌和抗肿瘤等方面都表现出良好的生物活性及药用价值。本文简要介绍具有7-氮杂吲哚结构化合物的生物活性。     

新型鬼臼毒素衍生物的合成及其抗肿瘤活性

目的 设计并合成新型鬼臼毒素类衍生物。方法 5-甲氧基吲哚与氯代物或酰氯反应得到一位氮取代的5-甲氧基吲哚;其与草酰氯反应,再以4-氨基4-脱氧表鬼臼毒素为原料,经缩合反应得到目标化合物。体外活性采用Hela细胞筛选模型进行评价。结果与结论 合成了7个新化合物,其中化合物7a, 7b 的活性优于阳性对照依托泊苷（etoposide）。     

吲哚衍生物的结构修饰及其抗乳腺癌作用研究进展

吲哚是平面杂环分子,对乳腺癌、肺癌、结肠癌等具有广泛的抗癌活性,在药物设计中发挥重要作用。从吲哚-3-甲醇及其代谢产物3,3′-二吲哚甲烷的结构修饰、吲哚骨架结构修饰、氧化吲哚衍生物及氮杂吲哚衍生物的结构修饰入手,并综合吲哚衍生物对Lumina型乳腺癌、三阴性乳腺癌、人表皮生长因子受体2(HER-2)过表达型乳腺癌的影响,从细胞水平、乳腺癌相关蛋白、受体、经典通路、体内外药理模型建立以及相关指标的变化等方面对其抗乳腺癌作用进行系统综述,以期为抗乳腺癌新药研发提供依据。     

吲哚美辛-PEG-1500酯的合成及体外抗肿瘤活性

目的合成吲哚美辛-聚乙二醇-1500(polyethylene glycol,PEG-1500)酯并考察其在水中的溶解度和体外抗肿瘤活性。方法通过吲哚美辛的羰基与PEG的羟基反应合成目标化合物羧酸酯;测定吲哚美辛-PEG-1500酯和吲哚美辛在水中的溶解度和熔点;以吲哚美辛原料药作为阳性对照药,采用MTT法测试目标化合物对HCT116人结肠癌细胞的生长抑制活性。结果合成的目标化合物的结构经IR、1H-NM R得到确证;吲哚美辛-PEG-1500酯比吲哚美辛有更好的水溶性;吲哚美辛和吲哚美辛-PEG-1500酯对HCT116人结肠癌细胞有相近的抑制作用。结论吲哚美辛-PEG-1500酯的合成不仅解决了IM C水溶性差的问题,而且也为其他同属于有机弱酸类且水溶性较差的药物解决相同或相似的问题提供了一个新的思路,具有较好的发展前景。     

九里香抗生育活性物质——月橘烯碱的仿生合成研究

月橘烯碱是从芸香科植物九里香根中分出的双吲哚生物碱。药理实验结果表明它具有抗着床和抗早孕的活性。本文报道其仿生合成:吲哚经3位醛基化、与丙酮缩合成化合物Ⅱ;将氮原子保护后进行wittig反应,脱保护基得到β-异戊二烯吲哚(Ⅴ);经分子间Diels-Alder加成反应得消旋月橘烯碱(Ⅵ)。     

吲哚美辛衍生物的合成及其抗炎活性

目的:合成吲哚美辛衍生物,以寻找新的对胃肠道毒不良反应更小的非甾体抗炎药.方法:吲哚美辛与卤代烃、硝基苄醇、硝基苄基氯等化合物进行缩合以及硝酸酯化反应,制备相应结构的衍生物.结果与结论:合成的6个化合物中,化合物3a,3c和5b的抗炎活性明显高于吲哚美辛.     

7-氮杂吲哚的合成

目的 研究医药中间体7-氮杂吲哚的合成方法.方法 以2-氨基-3-甲基吡啶为起始原料,经与二碳酸二叔丁酯反应保护2位氨基,然后在丁基锂的作用下得到二锂盐,二锂盐在稀盐酸中闭环反应,得7-氮杂吲哚.结果 反应总收率63%.结论 合成路线设计合理,条件温和,收率较好.     

九里香抗生育活性物质——月橘烯碱的仿生合成研究

月橘烯碱是从芸香科植物九里香根中分出的双吲哚生物碱。药理实验结果表明它具有抗着床和抗早孕的活性。本文报道其仿生合成:吲哚经3位醛基化、与丙酮缩合成化合物Ⅱ;将氮原子保护后进行wittig反应,脱保护基得到β-异戊二烯吲哚(Ⅴ);经分子间Diels-Alder加成反应得消旋月橘烯碱(Ⅵ)。     

一锅法合成新型吲哚-色胺酮类化合物

目的合成新型结构的吲哚-色胺酮[6-(1H-吲哚-2-基)吲哚并[2,1-b]喹唑啉-12(5H)-酮]类化合物,并初步考察其代表性化合物3a的抗肿瘤活性。方法以2-吲哚酮为起始原料,经盐酸酸化后在过量三氯氧磷的条件下与相应的取代2-氨基苯甲酸经一锅法合成新的吲哚-色胺酮类化合物。采用MTT法考察化合物3a对不同肿瘤细胞的抑制作用。结果与结论合成了3个未见报道的新化合物,目标化合物的结构经质谱、核磁共振谱确证。活性测试结果表明,化合物3a对A549肿瘤细胞株显示出一定的抑制作用。目标化合物是在色胺酮结构中引入吲哚单元后形成的新骨架结构的化合物,将为进一步研究基于吲哚-色胺酮结构的先导化合物提供一个新的方向。     

新型3-草酰胺-2-苯基吲哚衍生物的合成及其黄体细胞生长抑制活性的研究(英文)

本文报道以苯肼为原料合成了6个2-苯基-3-草酰胺基吲哚衍生物1a～f,其结构均未见文献报道。经初步体外试验结果表明,所被测试的6个目标化合物均具一定的离体黄体细胞生长抑制活性,且2-(4-甲氧苯基)吲哚化合物1b～d的活性明显高于2-苯基吲哚化合物1a。但在1b的吲哚氮上引入甲基或异丙基对活性没有影响。     

Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration

Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.     

Synthesis of analogs of L-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells.

L-Valacyclovir, a prodrug of acyclovir, is a substrate for the peptide transporter (PepT1) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity of L-valacyclovir for PepT1 is surprising, particularly when one considers that the molecule has the structural features of a nucleoside rather than a peptide. In an attempt to better understand the structure-transport relationships (STR) for the interactions of L-valacyclovir with PepT1, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepT1 in Caco-2 cell monolayers was determined. The analogs synthesized include those that had the guanine moiety of L-valacyclovir substituted with purine, benzimidazole, and 7-azaindole. All three analogs (purine, benzimidazole, and 7-azaindole) exhibited affinity for PepT1 in binding studies, but only the purine analog (as the L-valine ester) showed PepT1-associated transcellular transport across Caco-2 cell monolayers. The benzimidazole and 7-azaindole analogs (as their L-valine esters) were rapidly metabolized by esterase when applied to the apical surface of Caco-2 cells, which probably explains their low penetration as the intact prodrugs via PepT1.     

苯酰胺类c-Met激酶抑制剂的合成及其体外抗肿瘤活性研究

目的 设计和合成苯酰胺类c-Met激酶抑制剂,并测定其体外抗肿瘤活性。方法 以4-氯-6,7二甲氧基喹啉、6-氯-7-氮杂嘌呤和4-氯-7-氮杂吲哚为起始物,经取代、还原和缩合反应制备目标化合物3a~5c,并采用噻唑蓝法(MTT)测定目标化合物对GTL-16细胞的抑制作用。结果 合成了9个化合物,其结构经MS、1H-NMR和13C-NMR确证。化合物3a~5c对GTL-16细胞均呈现不同程度的抑制作用,其中化合物3c对GTL-16细胞的IC50达到411 nmol/L。结论 苯酰胺类化合物具有抑制GTL-16细胞活性的作用,值得进一步深入研究。     

Design, synthesis, and evaluation of 3,5-disubstituted 7-azaindoles as Trk inhibitors with anticancer and antiangiogenic activities

Tropomyosin-related kinase A (TrkA) is considered a promising target in the development of a therapeutic treatment of cancer and pain. In this study, we designed and synthesized a series of novel 7-azaindole-based Trk kinase inhibitors through the structure-based design strategy. By varying the functional groups at the 3 and 5 positions of a 7-azaindole scaffold, we studied the structure-activity relationships (SAR) profiles and identified a series of potent Trk inhibitors. Representative derivatives showed desirable activity in cellular proliferation and apoptosis assays. Moreover, these inhibitors exhibited noteworthy antiangiogenic activity.     

Discovery of 4-benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions

Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.     

Bis-imide granulatimide analogues as potent Checkpoint 1 kinase inhibitors

Granulatimide and isogranulatimide, natural products isolated from an ascidian, were found to be abrogators of the cell cycle G2-M phase checkpoint by inhibition of Checkpoint 1 kinase (Chk1). In the course of structure-activity relationship studies on granulatimide analogues, we have synthesized a series of bis-imides, in which the imidazole moiety was replaced by an imide heterocycle. Various modifications have been introduced on one or both imide heterocycles, on the benzene ring, and on the indole nitrogen. Moreover, aza bis-imide analogues were synthesized in which the indole moiety was replaced by a 7-azaindole. Compared to those of granulatimide and isogranulatimide, the Chk1 inhibitory activities of some of the bis-imide carbazoles were stronger. In particular, 1,3,4,6-tetrahydro-10-hydroxy-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone 11 exhibited an IC(50) value on purified full length Chk1 of 2 nM, which makes it a more potent Chk1 inhibitor than granulatimide and isogranulatimide. To get an insight into the selectivity of this new family of compounds, the inhibitory activities of 1,3,4,6-tetrahydro-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone A have been evaluated on a panel of 15 kinases, the strongest inhibitory potency was found for Chk1. The inhibitory activities of compounds A, 5 and 11 toward Src tyrosine kinase and the cytotoxicity of various tumor cell lines were also evaluated.     

Scaffold-hopping strategy: synthesis and biological evaluation of 5,6-fused bicyclic heteroaromatics to identify orally bioavailable anticancer agents

Utilizing scaffold-hopping drug-design strategy, we sought to identify a backup drug candidate for BPR0L075 (1), an indole-based anticancer agent. For this purpose, 5,6-fused bicyclic heteroaromatic scaffolds were designed and synthesized through shuffling of the nitrogen from the N-1 position or by insertion of one or two nitrogen atoms into the indole core of 1. Among these, 7-azaindole core 12 showed potent in vitro anticancer activity and improved oral bioavailability (F = 35%) compared with 1 (F < 10%).     

Metabolism of A dopamine D(4)-selective antagonist in rat, monkey, and humans: formation of A novel mercapturic acid adduct.

3-([4-(4-Chlorophenyl)piperazin-1-yl]-methyl)-1H-pyrrolo-2, 3-beta-pyridine (L-745,870) is a dopamine D(4) selective antagonist that has been studied as a potential treatment for schizophrenia, with the expectation that it would not exhibit the extrapyramidal side effects often observed with the use of classical antipsychotic agents. The metabolism of L-745,870 in vivo was investigated in the rat, rhesus monkey, and human using liquid chromatography-tandem mass spectrometry and/or NMR techniques in conjunction with radiochemical detection. In all three species, two major metabolic pathways were identified, namely N-dealkylation at the substituted piperazine moiety and the formation of a novel mercapturic acid adduct. It is proposed that the latter biotransformation process involves the formation of an electrophilic imine methide intermediate, analogous to that produced from 3-methyl indole. This report appears to represent the first example of metabolic activation of a 3-alkyl-7-azaindole nucleus.     

Structure-Based Drug Design of Novel,Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors

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“Walking the nitrogen around the ring”: Chemical synthesis and spectroscopic characterization of novel 4-, 5-, 6-, and 7-azaindazole analogs of the synthetic cannabinoid receptor agonist MDMB-PINACA

Over the past decade, synthetic cannabinoid receptor agonists (SCRAs) have rapidly evolved to encompass a wide range of structurally diverse new psychoactive substances (NPS), including derivatives that incorporate indole, indazole, 7-azaindole, γ-carbolinone, or carbazole heterocyclic scaffolds. The introduction of legislative measures seeking to control the availability of NPS on the recreational drug scene has likely contributed to the continued emergence of novel SCRA analogs, which often evade regulatory control. However, the detection and/or identification of azaindazole-type SCRAs in seized material has not yet been reported (September, 2021). It is plausible that SCRAs bearing a 1,3-disubstituted azaindazole scaffold may possess cannabimimetic activity, given their structural similarity with known indole, indazole, and azaindole SCRAs. In view of these antecedents, a set of four novel isomeric 4-, 5-, 6-, and 7-azaindazole analogs of the known potent indazole SCRA, MDMB-PINACA, were synthesized using a Pd-catalyzed aminocarbonylation strategy. The complementary use of ultraviolet (UV) and infrared (IR) spectroscopy, gas chromatography-mass spectrometry (GC-MS), high resolution mass spectrometry (HRMS), 1D- and 2D-nuclear magnetic resonance (NMR) spectroscopy, and high performance liquid chromatography (HPLC) has permitted the spectroscopic differentiation, unambiguous structural assignment, and rapid separation of novel isomeric 4-, 5-, 6-, and 7-azaindazole analogs of the indazole SCRA, MDMB-PINACA.