FAK mediated tumour cell migration, invasion, survival, proliferation and regulation of tumour stem cells through its kinase-dependent enzymatic functions and kinase-independent scaffolding functions. At present, the development of FAK PROTACs has become one of the hotspots in current pharmaceutical research to solve above problems. Herein, we designed and synthesised a series of FAK-targeting PROTACs consisted of PF-562271 derivative 1 and Pomalidomide. All compounds showed significant in vitro FAK kinase inhibitory activity, the IC50 value of the optimised PROTAC A13 was 26.4 nM. Further, A13 exhibited optimal protein degradation (85% degradation at 10 nM). Meantime, compared with PF-562271, PROTAC A13 exhibited better antiproliferative activity and anti-invasion ability in A549 cells. More, A13 had excellent plasma stability with T1/2 >194.8 min. There are various signs that PROTAC A13 could be useful as expand tool for studying functions of FAK in biological system and as potential therapeutic agents.
目的 对亚洲兰茂牛肝菌(Lanmaoa asiatica)内生真菌Penicillium cinereoatrum Chalab.JSQ-15的次级代谢产物进行分离与鉴定,并探究其细胞毒活性.方法 采用多种色谱技术分离纯化次级代谢产物,根据理化性质和波谱数据(质谱、核磁共振谱和Marfey分析)鉴定化合物结构,并采用噻唑蓝比色法(MTT法)评价其细胞毒活性.结果 与结论从内生真菌P.cinereoatrum Chalab.JSQ-15发酵产物中分离鉴定出18个化合物,分别为9(11)-去氢过氧化麦角甾醇(1)、过氧化麦角甾醇(2)、23-甲基过氧化麦角甾醇(3)、环(L-4-羟脯氨酸-L-亮氨酸)(4)、环(L-脯氨酸-L-亮氨酸)(5)、环(L-4-羟脯氨酸-L-苯丙氨酸)(6)、3-甲氧基-环(L-脯氨酸-L-亮氨酸)(7)、环(甘氨酸-L-脯氨酸)(8)、botryolide B(9)、decarestrictine I(10)、邻苯二酚(11)、5,6-二氢尿嘧啶(12)、2-哌啶酮(13)、trans-L-4-羟脯氨酸-L-亮氨酸(14)、1-亚油酰基溶血磷脂酰胆碱(15)、油酸-α-单甘油酯(16)、油酸(17)和丁二酸(18),18个化合物均为首次从P.cinereoatrum Chalab.中分离得到.化合物对肿瘤细胞的细胞毒活性测试结果表明:甾体类化合物1、2对小鼠小胶质细胞(BV2)、人肺癌细胞(A549)和人乳腺癌细胞(MCF-7)均呈现出较强的细胞毒活性(IC50≤30 μmol·L-1),化合物3、11对BV2细胞呈现出较强的细胞毒活性(IC50≤22μmol·L-1).本研究对亚洲兰茂牛肝菌内生真菌P.cinereoatrum Chalab.JSQ-15次级代谢产物进行了较为系统的分离鉴定,为该菌种次级代谢产物的首次报道.
目的 制备盐酸非索非那定杂质G,并对其安全性进行评价,为其质量标准研究提供依据.方法 以盐酸非索非那定为起始原料,经酸降解反应得到杂质G,并研究杂质G对小鼠细胞毒性、遗传毒性及生殖毒性的影响.结果 与结论盐酸非索非那定杂质G的结构经1H-NMR、13C-NMR、MS、IR、UV谱确证,其收率为57.35％,HPLC法检测纯度为98.23％.杂质G在0.25～2.00 mg·mL-1浓度范围内,随着浓度的增大,细胞毒性也逐渐增大;杂质G在40 mg·kg-1高剂量浓度下对小鼠骨髓细胞染色体无畸变作用,未显示对小鼠骨髓细胞染色体和微核有影响,且无致雄性小鼠生殖毒性作用.制备盐酸非索非那定杂质G的方法简便可行,评价杂质G对小鼠细胞毒性、遗传毒性及生殖毒性的方法真实有效.
应激颗粒(stress granule,SG)是细胞在遇到外界环境压力时形成的一种无膜细胞器.目前已经发现SG的组装和解体与多种疾病的发生发展过程密切相关,包括神经退行性疾病、癌症、病毒感染等,因此SG被认为是一个极具开发前景的潜在药物作用靶标.本文作者介绍了 SG的生物学特征及其与疾病发生发展的关系,并在此基础上对通过不同途径与机制干预SG组装或解体的化合物进行了归纳总结与评述,以期为SG作为药物靶点的可行性探讨以及靶向SG小分子化合物的研发提供参考.
To establish an affinity ultrafiltration mass spectrometry method for rapid screening of active components of Paeonia lactiflora,and to obtain it′s anticoagulant active components, the components of different polar parts of P.lactiflora were identified, and thrombin inhibitors in P.lactiflora were inverse-targeted screened by affinity ultrafiltration with thrombin（THR） as the target, and the obtained active components were analyzed and identified.Its activity was tested by chromogenic substrate method and in vitro anticoagulant method, and its binding ability was preliminarily analyzed by molecular docking.In this experiment, the active components in different polar parts of P.lactiflora were qualitatively analyzed, and 17 components were detected.An anticoagulant active component, ellagic acid, was screened by affinity ultrafiltration mass spectrometry.When the concentration of ellagic acid was 1 g·L -1 ,the inhibition rate of thrombin was 98.34%.In vitro coagulation experiments showed that the thrombin time（TT） of ellagic acid was significantly different from the blank group（P＜0.01）,indicating that it was a potential direct thrombin inhibitor.Molecular docking results showed that ellagic acid had many binding sites with thrombin activity, low binding energy, and good binding effect.The screening results showed that ellagic acid might be a potential thrombin inhibitor.At the same time, a rapid screening method for anticoagulant active ingredients in P.lactiflora was established, which provided valuable reference for targeted therapy, mechanism exploration and quality control of traditional Chinese medicine.
非奈利酮(finerenone,BAY 94-8862,1)是由拜耳公司开发的首个全新非甾体、高选择性盐皮质激素受体拮抗剂(MRA),可直接精准抑制盐皮质激素受体(MR)过度活化,发挥抗炎抗纤维化作用,进而带来肾心双重获益.该药于2021年7月9日经美国FDA批准上市[1],商品名为Ke-rendia.2022年6月28日,非奈利酮在中国上市,商品名为可申达,用于治疗由Ⅱ型糖尿病所致的成人慢性肾病.
Threonine tyrosine kinase（TTK）,also known as monopolar spindle 1（Mps1） kinase, is a core component of the spindle assembly checkpoint, which functions to ensure proper distribution of chromosomes to daughter cells.TTK is overexpressed in a variety of malignant tumor cells and selectively induces aneuploid tumor cell apoptosis, which makes TTK a potent target for cancer therapy.So far, a variety of small molecular TTK inhibitors with novel structures have been developed and even promoted into clinical trial phases.In this paper, the research progress of small molecule TTK inhibitors was summarized, their modes of action with TTK according to the structural features of the compounds were analyzed, the problems faced in the current research were discussed, and a prospect to the research direction in the future was given.This review will provide a reference for the research and development of new TTK inhibitors.
氘可来昔替尼(deucravacitinib)是由百时美施贵宝(Bristol-Myers Squibb,BMS)公司开发的酪氨酸激酶2(TYK2)抑制剂,于2022年9月9日经美国FDA批准上市,商品名为Sotyktu,用于治疗成人中度至重度斑块型银屑病(plaque psoriasis)等自身性免疫疾病[1].
神经退行性疾病是指神经元系统功能或结构的进行性和选择性丧失,可导致认知和运动功能障碍,包括阿尔兹海默症、帕金森病、亨廷顿病及肌萎缩侧索硬化症等.目前,神经退行性疾病仍缺乏有效的治疗手段,亟待开发新型抗神经退行性疾病的药物.蛋白降解靶向嵌合体(PROTAC)是一种新兴的蛋白质降解技术,其在包括神经退行性疾病在内的多种疾病中显示出强大的应用潜力.本文作者聚焦神经退行性疾病相关的PROTAC分子,对其结构、降解活性及药效进行了概括总结,并分析了其应用前景以及面临的机遇和挑战.
氢溴酸氘瑞米德韦是由中国科学院上海药物研究所、君实生物等共同研发的一款新型口服核苷类抗病毒药物,于2023年1月29日经国家药品监督管理局(NMPA)附条件批准上市,用于治疗成人轻中度新型冠状病毒感染(COVID-19)[1],商品名为民得维.
1H-1,2,3-Triazole ring derivatives were designed and synthesized from indole, and measured for anti-HBV activity in vitro.Fourteen target compounds were obtained from substituted indoles by substitution and cycloaddition reaction.The structures of the compounds were characterized by ~1H-NMR, 13 C-NMR and MS methods.HepG2.2.15 was used as a cell model to test the anti-HBV activity in vitro,and the effects of the compound on the secretion of hepatitis B surface antigen（HBsAg） and hepatitis B e antigen（HBeAg） in vitro were tested.Compounds 3c,3d,3m and 3n can inhibit the secretion of HBeAg and HBsAg.Meanwhile, compound 2-（4-（（5-chloro-1H-indol-1-yl）methyl）-1H-1,2,3-triazol-1-yl）ethyl acetate(IC 50 =75.41 μmol · L -1 ,SI=9.23) can better inhibit HBV DNA than other compounds synthesized.The indole 5-position halogen atom had obvious effect on inhibiting the secretion HBV.
With compound HBST144 as the lead compound, eight dual c-Met/VEGFR-2 inhibitors were designed, synthesized and evaluated for antitumor activities to study their preliminary SARs.The target compounds were prepared through different methods with mild conditions and high yields.The structures of the target compounds were identified by ~1H-NMR, 13 C-NMR and HR-MS.The results of biological evaluation indicated that compound 31e showed great potent inhibitory activities against both c-Met and VEGFR-2 with IC 50 values of 0.062 μmol·L -1 and 0.061 μmol·L -1 ,respectively, which was worthy of further study.
磷脂酰甘油类分子是甘油酯类衍生物,广泛应用于脂质体药物、脂质纳米颗粒(LNP)药物递送系统、小干扰核糖核酸(siRNA)药物等.本文作者基于对文献的总结以及对磷脂的结构分析,综述了磷脂酰甘油类分子的两种合成途径,即生物方法和化学方法.其中生物方法以磷脂酶D催化反应为主,化学方法主要包括两个片段的构建:由甘油衍生物合成二酰甘油酯,以及磷脂头部基团的构建.随着新型制剂的发展,磷脂酰甘油类分子作为核心辅料具有广阔的市场应用前景.
The synthesis process of PARP1 inhibitor AZD5305 was optimized in this study.With 6-methyl-5-nitro-nicotinic acid ethyl ester as the starting material, the intermediate 8 was obtained via condensation, oxidation, Wittig reaction, hydrogenation, oxidative dehydrogenation and reduction.With 2-bromopyridin-2-carboxylic acid methyl ester as the starting material, the intermediate 12 was prepared by catalytic coupling, ammonolysis and deprotection.Finally, the intermediate 8 was chlorinated and reacted with the intermediate 12 to produce AZD5305（1）.The structure of AZD5305 was confirmed by MS and NMR.This optimized process owns the advantages of milder conditions, simpler operation, lower costs, stable and controllable product quality, providing a reference for the industrial production.
莫努匹韦(molnupiravir,1)是全球首个上市的口服抗新型冠状病毒(SARS-CoV2)药物,其作用机制是抑制依赖RNA的RNA聚合酶(RdRp),进而抑制病毒核酸的合成,从而起到抗病毒作用.莫努匹韦是β-D-N4-羟基胞苷(EIDD-1931)的异丙酯前药,该前药进入血浆中迅速裂解为EIDD-1931,后分布到组织各处,经激酶磷酸化形成活性成分β-D-N4-羟基胞苷-三磷酸,并代替天然核苷酸被RNA合成酶识别并连接到病毒RNA链中,导致病毒基因组出现错误[1].
目的 对莱菔叶千里光(Senecio raphanifolius Wall.ex DC)的化学成分进行研究.方法 采用大孔吸附柱色谱、硅胶柱色谱、凝胶色谱、半制备高效液相色谱等技术对莱菔叶千里光乙醇提取物进行化学成分研究,根据波谱数据鉴定化合物结构.结果 从莱菔叶千里光中分离得到18个化合物,分别为异鼠李素-3-O-β-D-半乳糖苷(1)、香草酸-4-O-p-D-吡喃葡萄糖苷(2)、原儿茶酸(3)、5-羟甲基糠酸(4)、绿原酸(5)、苯基-p-D-葡萄糖苷(6)、绿原酸甲酯(7)、蓝花楹酮(8)、对羟基苯乙酸(9)、原儿茶醛(10)、对羟基苯乙酸甲酯(11)、芦丁(12)、千里光内酯(13)、6-羟基香豆素-4-羧酸(14)、油酸酰胺(15)、异鼠李素-3-O-葡萄糖苷(16)、1-O-β-D-吡喃半乳糖基甘油(17)、(±)-seneciphyllic acid lactone(18).结论 化合物2、4、6、13～15、17、18是首次从千里光属植物中分离得到,化合物14和18是首次从天然产物中发现.
目的 优化三苄糖苷的合成路线及工艺.方法 以1,2-O-异亚丙基-α-D-呋喃葡萄糖为起始原料,通过苄基保护、硫酸-乙酸-水混合溶剂中脱除异亚丙基、端位乙苷化共三步反应制备得到三苄糖苷.结果 与结论目标化合物的结构经ESI-MS、1H-NMR和13C-NMR谱确证,总收率为28.8％,HPLC纯度为99.61％,产品质量符合《欧洲药典》标准.该工艺在提高反应收率的同时,简化了实验操作,具有较高的实际应用价值.
In this study, through experimental demonstration, the reproduction of the patented method, and the confirmation of the structure, we disclosed the structure of the nitrosamine impurity API-NO,generated in the synthesis process of ticagrelor.The actual reaction process is that sodium nitrite reacts with ticagrelor to form the three-membered ring firstly, and then to form a stable five-membered ring structure（impurity 1）.Impurity 1 is a general impurity and has no mutagenicity, which will not interact with amine to form nitrosamine impurities.Residual levels of impurity 1 in the active pharmaceutical ingredient（API） were less than 10 -6 for multiple commercial production lots.
A series of novel 4-aminoquinazoline derivatives bearing 1-benzyl-1H-benzimidazole moiety were designed and synthesized.Taking 2-aminobenzoic acid as a starting matierial, intermediate 2-hydrazineyl-quinazolin-4-amine was obtained via cyclization, chlorination and two N-alkylation reactions.Meanwhile, intermediate 1-substituted benzyl-1H-benzimidazole-2-carbaldehyde was furnished by N-alkylation and formylation from benzimidazole.Finally, the target compounds（9a-9l） were synthesized through the condensation of the key intermediates.Most compounds exhibited good antitumor potency in vitro,the optimal compound 9l bearing 1-（4-methylbenzyl）-1H-benzimidazole with the IC 50 values of 0.51 μmol·L -1 and 0.93 μmol·L -1 against H-460 and A-549 cell lines, which was 11.7 and 5.2 times more active than gefitinib, respectively, had emerged as a lead for further study.
非苏拉赞(fexuprazan),化学名称为1-{5-(2,4-二氟苯基)-1-[(3-氟苯基)磺酰基]4-甲氧基-1H-吡咯-3-基}-N-甲基甲胺,分子式为C19H17 F3N2O3S,分子量为 410.41.Fexuprazan 的 Ⅲ 期临床数据在2020年消化疾病周(DDW)上由韩国大熊(Daewoong)制药公司首次公布,研究显示,fexuprazan为新型胃食管反流病药物,患者在使用后的第8周出现99％的胃黏膜愈合率,且耐受性好.同时,fexuprazan被证实具有显著抑制胃酸分泌的疗效,在缓解烧心以及其他非特异性症状上优于埃索美拉唑,而且缓解作用在夜间也持续存在[1-4].该药是一种新型的钾离子竞争性阻滞剂,其制备方法是重要的研究课题之一.
