非肽类蛋白酶抑制剂甲磺酸卡莫司他的合成

合成甲磺酸卡莫司他。将对胍基苯甲酸盐酸盐制备为酰氯,与对羟基苯乙酸-N, N-二甲基甲酰氨基甲酰甲酯在催化剂吡啶作用下制备甲磺酸卡莫司他,总收率为57.1%。获得高纯度的甲磺酸卡莫司他,本工艺适合工业化生产。     

卡莫司汀的合成

目的合成卡莫司汀。方法以尿素为原料,经缩合,开环,氯化,亚硝化而得。结果及结论此方法合成卡莫司汀原料易得,操作方便。     

司他夫定的合成

以2＇-溴-3＇,5＇-二乙酰基胸苷为原料,经Zn/AcOH催化的消除反应、水解脱乙酰基制得抗病毒药司他夫定,总收率约60%.     

依帕司他的合成

对醛搪还原酶抑制剂依帕司他的合成工艺作了改进，使中间体绕丹宁乙酸的收率提高到７６．４％。     

非达司他的合成

以对氟苯甲醚为原料,经傅—克酰化及分子内闭环反应制得(±)-6-氟-3,4-二氢-4-氧代-2H-1-苯并吡喃-2-甲酸(4),用(R)-N-苄基-1-苯乙胺(5)拆分得到(2S) -型的4a.再经Bucherer-Bergs反应、酯化及氨解反应制得非达司他,总收率约17％.     

司他夫定的合成

β-胸苷和对甲苯磺酰氯在吡啶中反应制得的3’，5’-二（对甲苯磺酰基）胸苷，在LiOH作用下醚化后，KOH-t-BuOH体系中进行β-消除反应制得司他夫定，总收率69％。     

GC-MS/MS法测定甲磺酸卡莫司他原料药中N-亚硝基二甲胺

目的建立GC-MS/MS法测定甲磺酸卡莫司他原料药中的亚硝胺类基因毒性杂质N-亚硝基二甲胺(NDMA)。方法采用Agilent DB-SELECT 624UI色谱柱(30 m×0.32 mm×1.80μm)色谱柱,离子源为EI源,采用多反应监测模式,以m/z 74→44.2为定量离子,m/z 74→42.2为定性离子,进行数据采集。结果 NDMA在12.571 2～100.569 6 ng/mL线性良好(r=0.997 6),检测限质量浓度为5.028 5 ng/mL,平均回收率为107.4%,RSD值为2.5%。结论该方法操作简单,灵敏度高,专属性和重复性好,可用于甲磺酸卡莫司他原料药中NDMA的检测。     

醛糖还原酶抑制剂非达司他的合成

目的：合成醛糖还原酶抑制剂非达司他。方法：以4-氟苯甲醚为起始原料，经傅克-酰基化取代、环合、酰氯化、拆分、水解、乙内酰脲化、醇酯化、氨解得目标化合物非达司他。结果：目标化合物经红外光谱、核磁共振氢谱、质谱确证其化学结构，总收率为14．5％。结论：在制备中间体2和7时，改进了工艺，提高了产率。     

非达司他的合成

对氟苯甲醚与马来酸酐缩合、碱性闭环得到(±)-6-氟-3,4-二氢-4-氧代-2H-1-苯并吡喃-2-羧酸,和氯化亚砜反应得到的酰氯与(S)-(-)-1-苯乙胺缩合,得到的酰胺差向异构体混合物利用乙醇重结晶拆分并水解得到单一对映体(2S)-6-氟-3,4-二氢-4-氧代-2H-1-苯并吡喃-2-羧酸,再经闭环、酯化、氨解等反应得到非达司他,总收率21%.     

天然多酚衍生物的合成、结构和酪氨酸酶抑制作用(英文)

以香草醛、茴香醛、染料木素和芦荟大黄素为原料合成一系列的衍生物,测定了衍生物(E)-1-(5-(4-甲氧基苯基)-3-(4-甲氧基苯乙烯基)-4,5-二氢-1H-吡唑-1-基)乙酮的晶体结构,并对这些化合物的酪氨酸酶抑制活性进行了测定。研究结果表明,香草醛、茴香醛、染料木素和芦荟大黄素的IC_(50)值分别为68μM,49μM,343μM和160μM。与标准对照品曲酸(IC_(50)=35μM)相比,香草醛衍生物(E)-1-(5-(4-甲氧基苯基)-3-(4-甲氧基苯乙烯基)-4,5-二氢-1H-吡唑-1-基)乙酮和芦荟大黄素衍生物4,5-二甲氧基-9,10-二氢蒽醌-2-甲酸具有更好的酪氨酸酶抑制活性,其IC_(50)值分别为18μM和21μM。     

C1-NH2-芳香基小诺霉素衍生物的合成

目的 发现新的抗菌药物.方法 本文对小诺霉素的C1-NH<,2>进行芳香化修饰,得到4个新衍生物[即:1-N-(4-甲基苄基)小诺霉素,1-N-(4-甲氧基苄基)小诺霉素,1-N-(2-呋喃基亚甲基)小诺霉素,1-N-(2-噻吩基亚甲基)小诺霉素].所有衍生物的结构经元素分析、IR、MS、<'1>H-NMR和<'13>C-NMR所确证,并进行了体外活性及急性毒性测试.结果 新衍生物活性不及小诺霉素,1-N-(2-呋喃基亚甲基)小诺霉素的急性毒性低于小诺霉素.结论 对以后相关工作具有启示作用和一定的参考价值.     

Synthesis of glabridin derivatives as tyrosinase inhibitors

A novel 3″,4″-dihydroglabridin was successfully prepared for studying on tyrosinase inhibitory activity. The result demonstrated that 3″,4″-dihydroglabridin exhibited higher activity than glabridin (IC₅₀ value = 11.40 μM), which is probably due to the 4-substituted resorcinol skeleton and the lacking of double bond between carbon atom 3″ and 4″ on its structure giving more conformational flexibily to interact with the enzyme more effectively. In addition, various acylated derivatives were synthesized as glabridin prodrugs. The chemical and enzymatic hydrolysis of prodrugs revealed that the diacetate ester was rapidly hydrolyzed by porcine liver esterase with the half-life of 2.36 minute, while those of the dihexanoate was 14.8 hour. Both of them were sufficiently stable in phosphate buffer, both pH 5.5 and 7.4, at 37°C with more than 15 days half-life.     

Synthesis and evaluation of some xanthone derivatives for anti-arrhythmic, hypotensive properties and their affinity for adrenergic receptors

A series of 2-, 4- or 2-methyl-6-substituted xanthone derivatives 8-17 containing selected piperazine moieties were synthesized and tested for their electrocardiographic, anti-arrhythmic, and antihypertensive activity, as well as for the alpha1- and beta1-adrenoceptor binding affinities. Of the newly synthesized derivatives, 2-(2-hydroxy-3-(4-(2-phenoxyethyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one dihydrochloride 9, 4-(2-hydroxy-3-(4-(2-phenoxyethyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one dihydrochloride 12, and 4-(2-(4-(pyridin-2-yl)piperazin-1-yl)ethoxy)-9H-xanthen-9-one dihydrochloride 15 possessed significant anti-arrhythmic activity in the adrenaline-induced model of arrhythmia, with the ED50 values ranging 1.7-7.2 mg/kg. Compound 15 had the lowest ED50 value equaling 1.7 mg/kg, which was comparable with ED50 value of propranolol, which was used in this test as a reference compound. Compound 9 showed also the strongest hypotensive activity, which persisted for 60 minutes at the dose of 2.5 mg/kg. 2-(2-(4-(2-Phenoxyethyl)piperazin-1-yl)ethoxy)-9H-xanthen-9-one dihydrochloride 8 also significantly lowered blood pressure at a dose of 2.5 mg/kg but much weaker than compound 9. Binding studies are in agreement with our pharmacological results and could explain anti-arrhythmic effect of compound 15 and anti-arrhythmic and hypotensive effects of compounds 9 and 12.     

Synthesis and in vitro cytotoxicity evaluation of novel naphthindolizinedione derivatives

Novel 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxamide derivatives and the corresponding 7,10-dihydroxy analogues were designed in accordance with Moore's and Pindur's theory and synthesized based on the structural similarity with known antitumour agents such as ellipticine, daunorubicin, mitoxantrone and 9-aminoacridine-4 carboxamide derivatives. These compounds, including structural variations of the amide side chain, were evaluated in the NCI panel of human tumour cell lines, from which 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-(2-dimethylamino-ethyl)-12-carboxamide 11a was found to be the most potent agent within the series. It showed good selectivity towards leukaemia, colon and renal cancer cell lines, with significant GI50 values, from lower than 10 nM to 0.2 microM. Moreover, its cytotoxicity against the adriamicine-resistant breast tumour cell line at a concentration lower than 1 microM turned out to be higher than the values using the clinical anticancer agents, daunorubicin and mitoxantrone.     

大黄素衍生物的合成及其应用研究进展

大黄素拥有利尿、引起血管舒张、抗菌、抗病毒、抗肿瘤等多种生物活性。但由于大黄素本身水溶性差、毒副作用大等缺点．近年来对大黄素的结构修饰得到了广泛的关注。本文综述了近年来国内外大黄素衍生物的最新合成进展,重点介绍一些具有较高生物活性的大黄素衍生物的合成报道。     

加贝酯的合成研究

报道了抗胰腺炎药加贝酯的合成方法，并对酰氯酯化法和二环己基碳二亚胺酯缩合法两条不同合成路线进行了比较，对中间体的制备，工艺改进和解决环境污染等问题进行了研究。     

Synthesis and cytotoxicity of kaempferol derivatives

In the present study, we developed a simple approach for the structural modifications of kaempferol (1). A new compound, 3,5-dihydroxy-2-(4-hydroxyphenyl)-6,8,8-tris(3-methylbut-2-en-1-yl)-4H-chromene-4,7(8H)-dione (5) together with three known compounds, 8-prenylkaempferol (2), 6-prenylkaempferol (3) and 6,8-diprenylkaempferol (4), were synthesized under different reaction conditions. All of derivatives were synthesized in a structural modification way for the first time. Their structures were primarily elucidated by NMR and MS analyses. Compounds 2, 3 and 5 exhibited prominent cytotoxic activity against MDA-231 (IC₅₀ values were 9.45±0.20μM, 7.15±0.37 μM and 6.92±0.30 μM, respectively) and MCF-7 (IC₅₀ values were 10.08±0.57μM, 10.04±0.23 μM and 2.15±0.20 μM,respectively) breast cancer cells.     

土槿乙酸衍生物的合成及其抗肿瘤活性

目的:研究土槿乙酸抗肿瘤作用的构效关系。方法:以土槿乙酸为原料,合成8个土槿乙酸衍生物,其结构经1H-NMR,MS证实。经MTT法筛选了衍生物的抗肿瘤活性。结果:8个化合物均为新化合物,除Ⅱc所有化合物均具有抗肿瘤活性,其中Ⅱf,Ⅱg的抗肿瘤活性显著高于土槿乙酸。结论:某些土槿乙酸酯和酰胺可提高抗肿瘤活性。