Synthesis of Pyrazole‐linked Norcantharidin Analogues of Substituted Chromones

Eighteen novel pyrazole‐linked norcantharidin derivatives substituted by chromone ring were synthesized in a single step by the [3+2] 1,3‐dipolar cycloaddition reaction of norcantharidin derivatives of substituted aromatic amines with hydrazone in the presence of chloramine‐T as compared to the conventional method.     

4-去甲斑蝥酰亚胺基丁酰苯硫脲的合成及抗惊厥活性

合成了11种γ-氨基丁酸异硫氰酯偶联去甲斑蝥素与取代苯胺目标化合物,其结构经IR、1HNMR和HR-MS测试技术确证。抗惊厥活性初步测定表明,化合物Ⅱ2、Ⅱ3和Ⅱ8显示了较强的抗惊厥活性。     

去甲斑蝥素四甲酸甲酯的合成工艺研究

聚酰亚胺是一类综合性能优异的耐高温胶黏剂,被广泛应用于航空航天及电子等高科技领域。去甲斑蝥素四甲酸单体进行聚合的聚酰亚胺可以降低分子刚性,这一特点引起了人们的注意。本文分别从钯催化剂的种类、CuCl2试剂的规格以及溶剂的级别等方面进行优化,最终发现在10%Pd/C,CuCl2试剂以及干燥处理过的甲醇溶剂条件下,以85%的较高收率得到去甲斑蝥素四甲酸甲酯单体。     

Determination and pharmacokinetic study of norcantharidin in human serum by HPLC-MS/MS method

A sensitive, simple and selective high-performance liquid chromatography-tandem mass spectrometry method was developed and applied to the determination of norcantharidin concentration in human serum. Norcantharidin (NCTD) and cyclophosphamide (IS) in serum were extracted with acetone, separated on a C18 reversed-phase column, gradiently eluted with a mobile phase of acetonitrile-water containing 2 mm ammonium acetate and 0.1% formic acid (pH 3), ionized by positive ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor-->product ions of m/z 169.3-->123.1 for NCTD and 261.2-->140.2 for IS, respectively. The linear range of the calibration curve for NCTD was 2.5-50 ng/mL, with a lowest limit of quantification of 2.5 ng/mL, and the intra/inter-day RSD was less than 10%. The method was suitable for determination of low NCTD concentration in human serum after therapeutic oral doses, and has been successfully used for pharmacokinetic studies in healthy Chinese volunteers.     

2D-QSAR Studies on the Norcantharidin Analogues as Protein Phosphatase 1 and 2A Inhibitors

The Two-dimensional Quantitative Structure-activity Relationship(2D-QSAR) of a series of novel norcantharidin analogues,which exhibit inhibitory activities of protein phosphatase 1 and 2A(PP1 and PP2A),has been studied with a combined method of ab initio(HF),molecular mechanics(MM+) and statistics.The established 2D-QSAR model(Eq.1) for PP1 shows a reasonable regressive performance(R2 = 0.749),and the hydrophobic property of this molecule plays a decisive role in determining the inhibitory activity of PP1.In addition,the established 2D-QSAR model(Eq.2) for PP2A also shows an acceptable regressive performance(R2 = 0.701),and the dipole moment of the molecule determines the inhibitory activity of PP2A.     

Strategies for Solubility and Bioavailability Enhancement and Toxicity Reduction of Norcantharidin

Cantharidin (CTD) is the main active ingredient isolated from Mylabris, and norcantharidin (NCTD) is a demethylated derivative of CTD, which has similar antitumor activity to CTD and lower toxicity than CTD. However, the clinical use of NCTD is limited due to its poor solubility, low bioavailability, and toxic effects on normal cells. To overcome these shortcomings, researchers have explored a number of strategies, such as chemical structural modifications, microsphere dispersion systems, and nanodrug delivery systems. This review summarizes the structure–activity relationship of NCTD and novel strategies to improve the solubility and bioavailability of NCTD as well as reduce the toxicity. This review can provide evidence for further research of NCTD.     

去甲斑蝥素-甘氨酸-取代苯胺硫脲的设计与合成及抗惊厥活性

癫痫是一种常见的神经系统疾病,它是脑神经元异常放电所致的突然、反复和短暂的中枢神经系统功能失常的慢性疾病和综合征.据流行病学调查,世界上大约有4千万到5千万人遭受癫痫疾病的折磨~([1]).我国目前癫痫患者人数有将近900万人之多,且每年有新发病例约40万.     

2D-QSAR Studies on the Norcantharidin Analogues as Protein Phosphatase I and 2A Inhibitors

The Two-dimensional Quantitative Structure-activity Relationship （2D-QSAR） of a series of novel norcantharidin analogues, which exhibit hnhibitory activities of protein phosphatase 1 and 2A （PP1 and PP2A）, has been studied with a combined method of ab initio （I/F）, molecular mechanics （MM＋） and statistics. The established 2D-QSAR model （Eq. 1） for PP1 shows a reasonable regressive performance （R2= 0.749）, and the hydrophobic property of this molecule plays a decisive role in determining the inhibitory activity of PP1. In addition, the established 2D-QSAR model （Eq. 2） for PP2A also shows an acceptable regressive performance （R2= 0.701）, and the dipole moment of the molecule determines the inhibitory activity of PP2A.     

Synthesis,Antiproliferative Activity and DNA-Binding Properties of Nitrogen and Sulfur Heterocyclic Norcantharidin Acylamide Acid

Three novel norcantharidin acylamide acids (L¹?N‐thiadiazole norcantharidin acylamide acid, C₁₀H₁₁N₃O₄S; L²?N‐thiazole norcantharidin acylamide acid, C₁₁H₁₂N₂O₄S and L³?N‐benzothiazole norcantharidin acylamide acid, C₁₅H₁₄N₂O₄S) were synthesized by the reactions of norcantharidin (NCTD?7‐oxabicyclo[2,2,1]heptane‐2,3‐dicarboxylic acid anhydride, C₈H₈O₄) with 2‐amino‐1,3,4‐thiadiazole (C₂H₃N₃S), 2‐aminothiazole (C₃H₄N₂S) and 2‐aminobenzothiazole (C₇H₆N₂S), respectively. Their structures were characterized by elemental analysis, IR, and NMR. The inhibition rates of L³ was much higher than those of L¹ and L² against human hepatoma cells SMMC7721 cell lines in vitro. The interaction between the compounds and DNA was studied by means of fluorescence quenching studies and viscosity measurements. The emission intensities decreased obviously with increasing concentration of the compounds in the fluorescence quenching experiments. The linear Stern‐Volmer quenching constant K_sq values were 0.62 (L¹), 0.55 (L²) and 1.08 (L³), respectively. The binding abilities followed the trend from high to low were L³, L¹ and L², respectively. The results of viscosity measurements showed that L¹ and L² might bind to DNA via partial intercalation, while L³ bound mainly in intercalation.     

7-氧杂双环[2.2.1]庚-2,3-二甲酸衍生物的合成及其抗HIV活性

以呋喃和顺丁烯二酸酐为原料,经环化反应制得7-氧杂双环[2.2.1]庚-5-烯-2,3-二甲酸酐(3);打开3的酸酐五元环,选择性地进行单酯化反应,合成了一系列7-氧杂双环[2.2.1]庚-3-烷氧羰基-2-甲酸(4a～4d),其结构经1H NMR和MS表征.初步探讨了4的抗HIV构效关系,其中4a的治疗指数与其先导化合物去甲基斑蝥素相当,毒性较之降低.