3-(4′-苯甲酰基氨基-苯基)-香豆素衍生物的合成及体外降血糖活性

首先以对氨基苯乙酸和水杨醛类化合物为原料,通过Perkin缩合反应,再经盐酸酸化合成了3个3-芳基香豆素类化合物4a~4c;再与取代苯甲酰氯6a~6h通过酰胺化反应合成得到了10个3-(4′-苯甲酰基氨基-苯基)香豆素类化合物7a~7j。所有目标化合物的结构均经过¹H NMR,¹³C NMR,ESI-MS进行了确证。通过测定α-葡萄糖苷酶抑制活性和晚期糖基化终产物(AGEs)形成抑制活性评价了目标化合物的体外降血糖活性。结果表明化合物7f(IC₅₀=10.84±0.36 μmol/L)表现出较好的α-葡萄糖苷酶的抑制活性;化合物7g(IC₅₀=5.01±0.55 μmol/L)对AGEs形成抑制活性远高于阳性药氨基胍盐酸盐(AG,IC₅₀=290.31±7.32 μmol/L),这些结果为抗糖尿病药物的进一步研究提供了理论基础。     

含1,2-苯并噻嗪结构的［1,3,4］噻二唑并［3,2-a］［1,3,5］三嗪衍生物的合成及其抗肿瘤活性

以吡罗昔康合成中间体(CAS:35511-15-0)为原料,利用活性拼接等药物设计原理,设计并合成了9个结构新颖的目标化合物,其结构经¹H NMR、MS等表征。通过测定对胰腺癌细胞Capan-1、白血病细胞L1210和人肝癌细胞SMMC-7721的抑制活性,评价目标化合物的体外抗肿瘤活性。结果表明,化合物6f(IC₅₀=2.4±0.5 μmol/L)对胰腺癌细胞Capan-1表现出较好的抑制活性;化合物6h(IC₅₀=5.4±0.2 μmol/L)对白血病细胞L1210表现出较好的抑制活性;化合物6g(IC₅₀=3.8±0.2 μmol/L)对人肝癌细胞SMMC-7721表现出较好的抑制活性。初步的抗肿瘤活性实验结果表明,将吡罗昔康3位的侧链替代为噻二唑并三嗪侧链,对提高该类化合物的抗肿瘤活性有一定的作用。     

含1,2-苯并噻嗪结构的咪唑并［1,2-b］［1,3,4］三氮唑衍生物的合成及其抗肿瘤活性

以吡罗昔康甲基物为原料,利用生物电子等排等药物设计原理,合成8个结构新颖的三氮唑化合物,其结构经¹H NMR、MS表征。通过测定对胰腺癌细胞Capan-1和白血病细胞L1210的抑制活性,评价目标化合物的体外抗肿瘤活性。结果表明,化合物6b(IC₅₀=3.6±0.5 μmol/L)对胰腺癌细胞Capan-1表现出较好的抑制活性;化合物6a(IC₅₀=1.8±0.2 μmol/L)对白血病细胞L1210表现出较好的抑制活性。初步的抗肿瘤活性实验结果表明,咪唑并三氮唑侧链的引入,对提高该类化合物的抗肿瘤活性有一定的作用。     

4-(N-芳基)胺基-6-长链烷氧基取代蝶啶类化合物的合成及其抗肿瘤活性

采用具有喹唑啉为母核的抗肿瘤药物作为先导化合物,利用生物电子等排原理,设计并合成一系列4-(N-芳基)胺基-6-长链烷氧基取代蝶啶类化合物7a~7l,并利用MTT法测试其对A549、KG1a和HGC-27肿瘤细胞的增殖抑制作用。以3-氨基吡嗪-2-羧酸甲酯为起始底物,通过6步反应合成12种目标化合物(7a~7l)并确证其结构(¹H NMR、¹³C NMR、MS)。生物活性试验表明,蝶啶4位为2-氯-5-硝基苯胺基取代时,其活性均高于其他苯胺基取代的产物。化合物7b对A549的活性(IC₅₀=11.55 μmol/L)与阳性对照物吉非替尼(IC₅₀=5.95 μmol/L)十分接近;化合物7k对3组细胞的IC₅₀均十分接近对照物吉非替尼。由于筛选出的化合物均有2-氯-5-硝基苯胺基片段,可以此结构为基础进行深入研究。     

含芳杂环取代的马蹄金素衍生物的设计、合成及抗乙肝病毒活性

以马蹄金素(MTS)为先导化合物,设计、合成了11个新的含芳杂环取代的马蹄金素衍生物,其结构经NMR、ESI-MS确认。采用HepG2 2.2.15细胞为乙肝病毒载体,评价目标化合物的抗HBV活性。结果表明,化合物7a［IC₅₀=2.94 μmol/L,选择指数(SI)=146.39］和9a(IC₅₀=2.21 μmol/L,SI>250)对HBV DNA复制的抑制活性高于先导化合物MTS(IC₅₀=11.16 μmol/L,SI=10.78),且具有更高的SI,提示该化合物在治疗HBV感染时具有更高的安全性,具有潜在的研究开发价值。     

新型熊果酸衍生物与查耳酮缀合物的合成及其抗肿瘤活性初步评价

以天然产物熊果酸为先导化合物,将查耳酮通过酯化反应拼接到熊果酸衍生物得到10个熊果酸衍生物-查耳酮缀合物,其结构均通过¹H NMR,¹³C NMR和HRMS加以确认。初步的生物活性结果表明,这些缀合物对CNE2、KB、MCF-7、A549和HepG2细胞均有抑制活性。特别是对MCF-7细胞的抑制活性强于熊果酸和临床上应用的药物他莫昔芬,其中化合物11e(IC₅₀=4.7 μmol/L)的抗乳腺癌活性最强,是他莫昔芬(IC₅₀=15.2 μmol/L)的近3倍;同时,这些缀合物对正常的MCF-10A和VERO细胞没有毒性,安全性较他莫昔芬高。     

3-苯基-3-吡咯基戊烷类化合物的合成及体外生物活性

以非开环甾体类维生素D受体(VDR)激动剂LG190155为先导物,通过结构改造设计合成了一系列3-苯基-3-吡咯基戊烷类化合物。通过测定目标化合物对HL-60细胞的促分化能力间接测定其对VDR的激动能力。结果表明,化合物13a,13c,13d,13h,13i,13j表现出较好的HL-60促分化活性(EC₅₀<50 μmol/L),提示这6个化合物具有较好的VDR激动能力。其中以化合物13j的促分化活性最高(EC₅₀=0.10 μmol/L),且优于先导化合物LG190155。采用MTT法评价目标化合物对VDR高表达的肿瘤细胞(人前列腺癌细胞PC-3、人乳腺癌细胞MCF-7、人结肠癌细胞Caco-2、人肝癌细胞HepG2)和人肝正常细胞(L02)的增殖抑制活性。结果表明,化合物13a在HepG2细胞株中的增殖抑制活性最好(IC₅₀=0.11 μmol/L),且对普通肝细胞L02的抑制作用较低(IC₅₀=15.24 μmol/L),说明化合物13a对肝肿瘤细胞具有一定选择性。此外还发现所合成化合物的促分化活性与抑制增殖活性成正相关。     

川芎嗪/查耳酮类杂合物的设计、合成及抗血小板聚集活性

基于药物设计的生物电子等排和拼合原理,设计、合成了一系列川芎嗪/查耳酮类杂合物(2~26),以期得到活性较强的抗血小板聚集药物。结果表明,目标化合物对二磷酸腺苷(ADP)和花生四烯酸(AA)诱导的血小板聚集均显示不同程度的抑制,其中化合物8活性最强,对ADP诱导的血小板聚集的抑制作用(IC₅₀=0.14 mmol/L)是川芎嗪的9.1倍,查耳酮的10.5倍;对AA诱导的血小板聚集的抑制作用(IC₅₀=0.09 mmol/L)是川芎嗪的8.8倍,查耳酮的10.0倍,且略优于阿司匹林(IC₅₀=0.15 mmol/L)。     

喹唑酮类甘氨酸转运体1抑制剂的设计、合成及药理活性研究

甘氨酸转运体1（GlyT1）是研究抗精神分裂症药物的靶点。以化合物2,4-二氯-N-{[4-（环丙甲基）-1-（乙磺酰基）哌啶-4-基]甲基}苯甲酰胺（1a,IC₅₀=92.2 nmol/L）为参考,设计并合成了未见文献报道的13个喹唑啉酮类化合物。初步药理活性实验结果表明,所合成的化合物除化合物7e外都具有一定程度的GlyT1抑制活性,其中化合物7j的活性最强,接近阳性对照药1a。     

4-(3-磺酰基苯基)氨基-6-甲酰基吡咯并［2,3-d］嘧啶类化合物的设计、合成与生物活性

以JAK2抑制剂baricitinib和fedratinib为先导化合物,运用分子杂交药物设计原理,设计并合成了17个以4-(3-磺酰基苯基)氨基-6-甲酰基吡咯并［2,3-d］嘧啶(3)为母核、结构新颖的目标化合物,并通过JAK2激酶和粒细胞-巨噬细胞集落刺激因子(GM-CSF)诱导的TF-1细胞对所合成的化合物进行了活性测试。结果显示,多数化合物具有JAK2抑制活性,其中化合物(31)表现出较好的JAK2激酶活性(IC₅₀=0.009 μmol/L)和GM-CSF诱导的TF-1细胞抑制活性(IC₅₀=0.136 μmol/L),表明该化合物具有潜在的研发价值。     

APPLICATION OF LORNOXICAM TO PATIENT-CONTROLLED ANALGESIA IN PATIENTS UNDERGOING ABDOMINAL SURGERIES

FOR anesthesiologis s ,treatingpostoperativepainhas alwaysbeen a problem.Althoughopioidshave been provedtobe effective,theirsideeffectscouldnotbeignored.With thedevelopmentofscienceand pharmacology,many drugs with aspectsof satisfactoryanalgesicefficacyand couldbe welltoleratedby patientshave been developed.And lornoxicamisone of them, which isa non-steroidalanti-inflammatorydrug (NSAID ), with analgesic, anti-infl-ammatory,andantipyreticproperties.Itseliminationhalf-time(3 to 5 hours) isle…     

Value of D-Dimers in patients with acute aortic dissection

Objective: To evaluatel the value of D-dimers in patients with acute aortic dissection (AAD). Methods: This study consisted of 16 patients with AAD and 27 non-AAD patients. Serum D-dimets were measured by Sta-Liatest D-DI immunoturbidimetric assay. Results: D-dimer level was higher (P ＜ 0.001) in patients with AAD(7.91 ± 5.52 μg/ml) than that in non- AAD group(1.57±1.24 μg/ml). D-dimer was positive (＞0.4 μg/ml) in all patients with AAD and in 10 control group patients (37%). Among patients with acute AAD, D-dimers tended to be higher in Stanford A than in Stanford B (8.67 ± 4.31 μg/ml vs. 3.24±1.27 μg/ml, P ＜0.01). D-dimer values tended to be higher in more extended disease(3.84 ± 1.65 μg/ml, 8.57 ± 3.58 μg/ml and 11.87 ± 5.69 μg/ml in thoracic aorta, thoracic and abdominal aorta, thoracic and abdominal aorta and iliacal arteries, respectively, P ＜ 0.05 for both 8.57 ± 3.58 and 11.87 ± 5.69 vs. 3.84 ± 1.65 ). Including the control group into the analysis, we found a sensitivity of 100%, a negative predictive value of 100%, and a specificity of 66% and a positive predictive value of 64% for D-dimer in diagnosis of AAD in our patients with suspected AAD. Conclusion: D-dimer was elevated in patients with AAD. A negative D-dimer test result could be useful in excluding AAD.     

Research of combined liver-kidney transplantation model in rats

Objective： To set up a simple and reliable rat model of combined liver-kidney transplantation. Methods： SD rats served as both donors and recipients. 4℃ sodium lactate Ringer＇s was infused from portal veins to donated livers,and from abdominal aorta to donated kidneys, respectively. Anastomosis of the portal vein and the inferior vena cava （IVC） inferior to the right kidney between the graft and the recipient was performed by a double cuff method, then the superior hepatic vena cava with suture. A patch of donated renal artery was anastomosed to the recipient abdominal aorta. The urethra and bile duct were reconstructed with a simple inside bracket. Results： Among 65 cases of combined liver-kidney transplantation, the success rate in the late 40 cases was 77.5%. The function of the grafted liver and kidney remained normal. Conclusion： This rat model of combined liver-kidney transplantation can be established in common laboratory conditions with high success rate and meet the needs of renal transplantation experiment.     

Development on Adjustable Calibration Marker for Shock Wave Focus

Shock wave lithotripsy （SWL） is a treatment of choice for upper urinary stones. However, this procedure is inappropriate for obese patients because the focus is often unable to reach the target owing to the limited focal distance in shock wave source. Although treating such patients in a blast path may increase the application length of shock wave source, it＇s difficult to find this path on the lithotripter monitor. For this reason, we invented an adjustable calibration marker in order to set an effective focus in the shock wave hath.     

Study on the TCM Pathogenesis of Angiopathic Complications of Type II Diabetes

Excess production of reactive oxygen species(ROS)of mitochondrion mediated by hyperglycemia is the common pathogenesis of angiopathic complications of diabetes.TCM holds that the damp from the dysfunction of spleen.kidney and liver is the causative factor of complications of diabetes.This is similar to the mechanism of Ros resulting in angiopathic complications of diabetes.When the angiopathic complications of type II diabetes mellitus(T2DM)are difierentiated as caused by turbid damp in TCM can be explained as ROS.Since the obstruction of pathogenic damp in channels and collaterals is said to be the main pathogenesis,the treating principle should be dissolving the damp to remove the obstruction.     

Leptin, Ghrelin and TNF-α before and after Hypo-caloric Traditional Chinese Diet and Auricular Acupuncture

INTRODUCTION Obesity is a complex emergent problem, which can be possibly solved not only by the diet but also by the life style and promotion of a constant physical exercise. 1, 2 No doubt careful attentions must be given to the nutritional condition of obese people, the dietary habits, the somatic build (i.e. distribution of fat mass) and the organic functions linked to formation of the fat mass. All the parameters should be constantly monitored before, during and after a diet treatment. 3, 4, 5     

BLOOD PRESSURE CHANGE WITH AGE IN SALT-SENSITIVE TEENAGERS

Objective To observe blood pressure change with age in salt-sensitive teenagers whose salt sensitivity were determined by repeated testing.Methods Salt sensitivity was determined through intravenous infusion of normal saline combined with volume-depletion by oral diuretic furosemide in 55 teenagers. After five years, salt sensitivity was re-examined and subject blood pressure was followed up. Blood pressure changes in salt-sensitive teenagers were compared to that of non-salt sensitive teenagers over five years.Results After 5 years, the repetition rate of salt sensitivity determined by intravenous saline loading is 92.7%. In teenagers with salt sensitivity on the baseline, both the systolic blood pressure increments and increment rates were much higher than non-salt sensitive teenagers (12.7±12.1 mmHg vs. 2.8±5.2 mmHg, P＜ 0.01; 12.2%± 12.0% vs. 2.5% ±4.4%, P＜ 0.001,respectively). There was a similar trend for diastolic blood pressure (8.4 ± 6.4 mmHg vs. 3.7 ± 6.4 mmHg, P = 0.052; 13.2% ±10.6 % vs. 6.8%± 10.1%, P = 0.053, respectively).Conclusions Salt sensitivity determined by intravenous saline loading showed good reproducibility. Blood pressure increments with age were much higher in salt-sensitive teenagers than non-salt sensitive teenagers, especially in terms of systolic blood pressure.     

Relationship between Dysglycemia and Carotid Atherosclerosis in Tibetan Population

People with dysglycemia are at high risk for atherosclerotic diseases. This study aims at investigating the atherosclerotic vascular damage in dysglycemia and its metabolic origin in Tibetan population.     

Acupuncture Combined with Spinal Tui Na for Treatment of Primary Dysmenorrhea in 30 Cases

Objective: To observe the therapeutic effects in acupunture treatment of primary dysmenorrhea combined with spinal Tui Na, and study its mechanism. Methods: Thirty cases of the treatment group were treated by acupuncture combined with spinal Tui Na, and thirty cases in the control group were treated by routine acupuncture. Results: The total effective rate was 93.3% in the treatment group, and 73.3% in the control group, with a significant difference between the two groups (P<0.05). Conclusions: Acupuncture combined with spinal Tui Na has good prospects for treatment of primary dysmenorrhea.     

Luo Lingjie's Experience in Treating Chronic Nephropathy

In treating chronic nephropathy,Luo Lingjie,a chief physician,pays attention to regulating the balance between yin and yang,treating infection if present,and removing pathogenic factors.He prescribes gentle drugs and uses carefully strongly warming-tonifying ones,emphasizes the importance of persuading the patient to persist in treatment with medication and nurse one's health for recuperation,and is good at combined use of TCM and western medicine therapy and brings the merits of various therapies into full play,with obvious theraoeutic effects.