新型环磷酰胺前药:环磷酰胺哌嗪季铵盐的构效关系(英文)

作为对环磷酰胺结构改造新思路的延续, 本文以化合物9i为先导物设计并合成了三个系列环磷酰胺哌嗪季铵盐类衍生物(10, 11和13)。通过体内抗肿瘤活性试验, 其构效关系表明: 1)环磷酰胺螺环哌嗪季铵盐(10)的构象和N-3位的取代基对活性影响极大2)不同类型的环磷酰胺非螺环哌嗪季铵盐(11)显示出其抗肿瘤活性的差异 3) 选择合适的季铵盐部分, 化合物1,2-苯并异恶唑磷酰哌嗪季铵盐(13)有可能具有抗肿瘤活性。此研究结果将有助于进一步设计和改造各种氮芥类抗肿瘤药物。     

二酰基双哌嗪双季铵盐类衍生物的合成及镇痛活性

目的：寻找活性强,毒性低的新型镇痛药物。方法：以1-甲基哌嗪为起始原料, 通过与不同的二酰氯反应得双二酰基哌嗪(IIIa-d), IIIa-d分别用不同的溴化物季铵化得6个新的1,1-二酰基-4,4,4′,4′-四烷基双哌嗪双季铵盐溴化物(IVa-f)。 结果：初步生物活性试验结果表明,这些化合物均有一定的镇痛和镇静活性, 尤其是IVe(剂量20 mg.kg^-1, 镇痛活性80.3%,镇静活性95.3%)和IVf(剂量0.5 mg.kg^-1, 镇痛活性75.5%,镇静活性53.8%)活性显著。结论：构效关系研究表明,两个季氮原子之间的距离对活性和毒性有较大影响,当n=4时, 活性最强,而毒性随两个季氮原子之间距离的减小而降低。苄基的引入可使活性明显增强,而且毒性降低。     

1,6-二(4-苯乙基-1-甲基-1-哌嗪基)己烷二溴化物镇痛作用及机制探讨

目的　研究哌嗪类新化合物1,6-二( 4-苯乙基1-甲基-1-哌嗪基)己烷二溴化物(97-9-G4)的镇痛作用及机制。方法　扭体法、热板法研究镇痛活性;联合给药观察纳洛酮、利血平、阿托品、CaCl₂和EDTA等对97-9G4镇痛作用的影响;并测定97-9-G4对小鼠体内PGE₂的影响。结果　sc 97-9-G4 5mg/kg即可有效抑制小鼠扭体反应(P<0.05) ;sc 40mg/kg和icv 2.5μg/kg均可明显延长热板实验的舔足阈(P<0.05) ;纳洛酮、CaCl₂和EDTA均可拮抗、减弱或加强其镇痛作用;利血平、阿托品对97-9-G4的镇痛作用影响不明显。结论　97-9-G4具有明显的镇痛活性,其镇痛作用与阿片受体及体内Ca²⁺等因素有一定关系。     

抗消化性溃疡病药物杂环甲醛缩N4-取代苯基氨(硫)脲的合成和定量构效分析

按类型衍化出的先导物结构,经逐步调整苯环上取代基的电性和疏水性,合成了45个呋喃、吡咯和N-甲基吡咯-α-甲醛缩N⁴-3-,或4-取代的苯基氨脲和氨硫脲。对抗溃疡作用和毒性作用的定量评价及构效分析表明,活性与疏水性呈抛物线关系;引入推电子基团,有利于抗溃疡活性。化合物17和30的活性与毒性的分离较大,其药理作用在深入研究中。     

R,S-1-(取代苯基)-4-[3-(萘-1-氧基)-2-羟基丙基]哌嗪类化合物的设计、合成及血管舒张活性

设计合成具有血管舒张活性的苯基哌嗪类系列化合物。以naftopidil活性代谢产物为先导化合物，根据已报道的苯基哌嗪类α₁-受体拮抗剂构效关系研究结论对先导化合物进行结构优化，设计并合成一系列新的苯基哌嗪类化合物，确定其结构，并通过测定其对苯肾上腺素引起家兔胸主动脉条收缩的抑制作用评价其血管舒张活性。发现其中5个化合物显示出不同程度的活性，其中化合物16的血管舒张活性较强，其在0.01和1 μmol·L^-1条件下血管收缩抑制率分别达到7.03%和22.72%，化合物16拟采用自发性高血压大鼠降压试验等进行进一步抗高血压活性研究。以上研究提示已报道苯基哌嗪类化合物的构效关系研究结论可适合于naftopidil的结构修饰。     

四氢喹啉类化合物的合成及其镇痛活性研究

目的寻找具有镇痛活性的新型四氢喹啉类化合物,探讨4-（1H-吡咯-2-基）-1,2,3,4-四氢喹啉类化合物镇痛作用的构效关系。方法以4-（1H-吡咯-2-基）-1,2,3,4-四氢喹啉类化合物为母体,合成系列化合物。用醋酸致小鼠扭体法测定该类化合物的镇痛活性。结果与结论合成了20个新化合物,经1H-NMR和MS确证其结构。镇痛活性试验表明,所合成的部分化合物具有明显的镇痛作用,值得进一步研究。     

1-烷基-1-苄基-4-(3-氯-2-羟基)丙基哌嗪季铵盐的合成及生物活性

设计合成了7个1-烷基-1-苄基-4-(3-氯-2-羟基)丙基哌嗪季铵盐(Ia～g)。生物活性试验结果表明,苄基苯环上连有强吸电子取代基时,可使抗炎和镇痛活性明显增强;季铵盐中的负离子对生物活性有一定的影响。在20mg·kg^-1的剂量下,Id和Ie的抗炎活性和Ie的镇痛活性明显。     

6—｛４—[4—（取代苯乙酮基）哌嗪基]苯基｝—5—甲基—4，5—二氢—3（2H）哒嗪

根据哒嗪酮类化合物的构效关系和作用机制。以CCI17810为先导经合物,设计合成了6-[4-（取代哌嗪基）苯基]-5-甲基-4,5-二氢-3（2H）哒嗪酮类化合的12个,初步的体外药理试验表明,大部分目标化合物箸阴不同程度的抑制ADP诱导的新西兰大白兔血小板聚集的作用,其中化合物（4）的活性最强,比先导化合物CCI17810大约经一倍,化合物（1）,（2）,（11）也有较强的活性。     

1-阿魏酰基-4-取代苄基哌嗪盐酸盐的合成及其清除羟自由基活性

以阿魏酸、哌嗪和取代氯苄为原料,合成了11个结构新颖的1-阿魏酰基-4-取代苄基哌嗪盐酸盐;用邻二氮菲-Fe2+氧化法测定目标化合物的体外清除羟自由基活性。结果显示11个目标化合物均具有不同程度的清除羟自由基活性,并初步讨论其构效关系。     

抗支原体喹诺酮的合成及其构效关系

目的：开发新型抗支原体药物。方法与结果：设计合成了一系列新型左旋氧氟沙星类似物(18～24)，测试其体外抗支原体活性(MIC值)，并讨论了他们的构效关系。结论：所合成的化合物有较好的抗支原体活性。哌嗪环或高哌嗪环4位氮原子有吸电子基团时，可能有利于提高喹诺酮的抗支原体活性。     

Investigation of cis/trans proline isomerism in a multiply occurring peptide fragment from human salivary proline-rich glycoprotein

The solution-state conformations of eight proline-containing peptide fragments found in human salivary proline-rich glycoprotein (PRG) were investigated in 2 × distilled water (treated with metal ion chelating resin) using ¹³C-nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy. The peptide sequences and acronyms were as follows: PRG9-2 = NH₂-G(I)-P(2)-CONH₂, PRG9-3 = NH₂-G(1)-P(2)-P(3)-CONH₂,PRG9-4 = NH₂-G(1)-P(2)-P(3)-P(4)-CONH₂, PRG9-5 = NH₂-G(1)-P(2)-P(3)-P(4)-H(5)-CONH₂,PRG9-6 = NH₂-G(1)-P(2)-P(3)-P(4)-H(5)-P(6)-CONH₂, PRG9-7 = NH₂-G(1)-P(2)-P(3)-P(4)-H(5)-P(6)-G(7)-CONH₂, PRG9-8 = NH₂-G(1)-P(2)-P(3)-P(4)-H(5)-P(6)-G(7)-K(8)-CONH₂ and PRG9-9 = NH₂-G(1)-P(2)-P(3)-P(4)-H(5)-P(6)-G(7)-K(8)-P(9)-CONH₂. Sequence-specific resonance assignments from the ¹³C-NMR spectra indicated that the trans proline isomer dominated the conformations of the peptides. CD results clearly showed the presence of the poly-l -proline II helix as the major conformation in PRG9-3 → PRG9-5, supplemented by β- and/or γ-turns in PRG9-6 → PRG9-9. These data suggest that in “metal free” water, native PRG could contain several small poly-l -proline II helices along with β- and/or γ-turns. Since proline is the major amino acid present in native PRG, these localized conformations may contribute to PRG's global conformation and act as a primary force in determining its biological activities.     

特比萘芬与复方酮康唑治疗皮肤真菌病的比较

目的 :特比萘芬与复方酮康唑治疗皮肤真菌病的疗效比较。方法 :患浅部真菌病病人 6 0例 ,男性 4 1例 ,女性 19例 ,年龄 (2 9±s 9)a ,随机分为特比萘芬组 30例 ,应用特比萘芬软膏外涂患处 ,bid× 2wk ;复方酮康唑组 30例 ,外用复方酮康唑霜剂 ,bid× 2wk ;在停药时及停药 2wk后观察疗效。结果 :治疗结束时 ,特比萘芬组总有效率为 73% (2 2 /30 ) ,复方酮康唑组为 57% (17/30 ) ,P >0 .0 5;停药 2wk后 ,特比萘芬组总有效率为 97% (2 9/30 ) ,复方酮康唑组为 4 7% (14/30 ) ,P <0 .0 5。治疗结束时 ,特比萘芬组真菌清除率为 83% ,复方酮康唑组为 53% ,P <0 .0 5,停药 2wk后 ,特比萘芬组真菌清除率为 97% (复方酮康唑组为 37% ,P <0 .0 1)。 2组均未见不良反应。结论 :特比萘芬治疗浅部真菌病优于复方酮康唑。     

The food mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline: a conformational analysis of its major DNA adduct and comparison with the 2-amino-3-methylimidazo[4,5-f]quinoline adduct

The heterocyclic amine 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is one of a group of heterocyclic amine carcinogens that exists in cooked meat and fish. It causes mutations in bacterial and mammalian assays and induces tumors in mammals. MeIQx is converted within cells to a reactive derivative which forms a major covalent adduct at carbon-8 of guanine in DNA. This adduct may alter the DNA conformation at critical stages of the replicative process, and cause mutations which initiate the carcinogenic process. Atomic resolution structures of the MeIQx-damaged DNA are not yet available experimentally. We have carried out an extensive molecular mechanics/energy minimization search to locate feasible structures for the major MeIQx adduct in DNA, using the sequence d(5'-C1-G2-C3-G4[IQ]-C5-G6-C7-3').d(5'-G8-C9-G10-C11-G12-C13-G14-3') with MeIQx modification at G4. We have created 1152 starting conformations which uniformly sampled each of the three flexible torsion angles that govern the MeIQx-DNA orientation at 15 degrees intervals, and minimized their energy. A mixture of conformations was generated, which were separated into families according to the position of the ring system of the carcinogenic amine: major groove, minor groove, and base-displaced-intercalated. While a generally similar mixture had been generated previously for the related carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) [Wu, X., et al. (1999) Chem. Res. Toxicol. 12, 895-905], differences were found which could be rationalized in terms of the additional methyl group in the MeIQx.     

Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery

In this study an advanced multisampling site pig model, with simultaneous venous blood sampling pre- and post liver, was applied to quantify the role of the intestine in relation to the liver in first-pass glucuronidation of raloxifene in vivo. The pharmacokinetic of raloxifene (a BCS/BDDCS class II compound) in humans is characterized by extensive metabolism (>90%) and the major metabolite is the 4'-β-glucuronide (R-4-G). Following intra-jejunal (i.j.) single dose administration in pigs raloxifene was metabolized in the gut (E(G)) during first-pass to more than 70% and a high concentration (AUC(0-6 h) ratio R-4-G/raloxifene >100) of R-4-G was reached in the portal vein. The hepatic extraction (E(H)) of raloxifene was ~50% and as in humans the bioavailability become low (~7%) in pigs. Interestingly the E(H) of raloxifene and R-4-G was time-dependent after i.j. administration. It is clear that the gut was the dominating organ in first-pass extraction of raloxifene in vivo in pigs. The quantification in this study support earlier human data and emphasize that intestinal glucuronidation should be considered early in the pharmaceutical development.     

Conformational analysis of the major DNA adduct derived from the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline.

The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is one of a number of carcinogens found in barbecued meat and fish. It is mutagenic in bacterial and mammalian assays and induces tumors in mammals. IQ is biochemically activated to a derivative which reacts with DNA to form a major covalent adduct at carbon 8 of guanine. This adduct may deform the DNA and consequently cause a mutation, which may be responsible for initiating IQ's carcinogenicity. Atomic resolution structures of the IQ-damaged DNA are not yet available experimentally. We have carried out an extensive molecular mechanics energy minimization search to locate feasible structures for the major IQ-DNA adduct in the representative sequence d(5'-G1-G2-C3-G4-C5-C6-A7-3'). d(5'-T8-G9-G10-C11-G12-C13-C14-3') with IQ modification at G4; this contains the GGCGCC mutational hotspot sequence known as NarI. The molecular mechanics program AMBER 5.0 with the force field of Cornell et al. [(1995) J. Am. Chem. Soc. 117, 5179-5197] was employed, including explicit Na(+) counterions and an implicit treatment for solvation. However, key parameters, the partial charges, bond lengths, bond angles, and dihedral parameters of the modified residue, are not available in the AMBER database. We carefully parametrized the force field, created 800 starting conformations which uniformly sampled at 18 degrees intervals each of the three flexible torsion angles that govern the IQ-DNA orientation, and minimized their energy. A conformational mix of structural types, including major groove, minor groove, and base-displaced intercalated carcinogen positions, was generated. This mixture may be related to the diversity of mutational outcomes induced by IQ.     

Interindividual variation in the ratio between plasma morphine and its metabolites in cancer patients

In 25 cancer patients treated with slow-release oral morphine and in 10 cancer patients treated with continuous infusion of morphine, plasma steady-state concentrations of morphine (M), morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) were determined by high-performance liquid chromatography. Blood samples were withdrawn at 0, 2 and 6 h after oral administration in patients treated with slow-release oral morphine and once or twice a day in patients treated with continuous infusion of morphine. In four cancer patients treated with continuous infusion of morphine, in order to analyze chronopharmacokinetic variability, the M-3-G/M ratio was observed at 12:00 h and 24:00 h. No significant changes were observed in M-3-G/M ratios and M-6-G ratios at 0, 2, and 6 h after oral administration of morphine. The M-3-G/M ratio (38.6 +/- 25.7) in the oral morphine group was significantly higher than that (15.3 +/- 12.9) in the continuous infusion group (p < 0.01). There was an approximately 10-fold interindividual variation in the M-3-G/M ratio both in the continuous infusion group and in the oral morphine group. These results suggest that the activity of UDP glucuronosyltransferase 2B7 in the intestinal metabolism of morphine may play an active part in a large interindividual variation in the ratio of metabolites to morphine. Further studies are needed to clarify this hypothesis.     

复方卡尼汀对血小板GMP140和β血小板球蛋白含量的影响

目的 :了解复方卡尼汀对肝硬化病人血浆中GMP 140及 β TG的影响。方法 :79例肝硬化病人随机分为 2组 ,对照组 4 0例 ,用常规 (10 %葡萄糖注射液 50 0mL +能量合剂 2支 +10 %氯化钾 10mL ,iv ,gtt,qd× 4wk)治疗 ,治疗组 39例 ,在常规治疗基础上加用复方卡尼汀 2支 ,iv ,gtt ,qd× 4wk。结果 :治疗组与对照组总有效率分别为 97%和 6 8%(P <0 .0 5)。治疗前后GMP 140和 β TG的差值 ,治疗组分别为 :(- 30 0 2± 1389) μg·L- 1,(- 2 7±2 2 ) μg·L- 1;对照组分别为 :(- 911± 1318) μg·L- 1,(8± 7) μg·L- 1,均P <0 .0 1。结论 :复方卡尼汀具有降低血浆中GMP 140及 β TG的含量 ,有效改善肝功能的作用     

Mechanistic Studies on the Absorption and Disposition of Scutellarin in Humans: Selective OATP2B1-Mediated Hepatic Uptake Is a Likely Key Determinant for Its Unique Pharmacokinetic Characteristics

Scutellarin [scutellarein-7-O-glucuronide (S-7-G)] displayed a unique pharmacokinetic profile in humans after oral administration: the original compound was hardly detected, whereas its isomeric metabolite isoscutellarin [scutellarein-6-O-glucuronide (S-6-G)] had a markedly high exposure. Previous rat study revealed that S-7-G and S-6-G in the blood mainly originated from their aglycone in enterocytes, and that the S-7-G/S-6-G ratio declined dramatically because of a higher hepatic elimination of S-7-G. In the present study, metabolite profiling in human excreta demonstrated that the major metabolic pathway for S-6-G and S-7-G was through further glucuronidation. To further understand the cause for the exposure difference between S-7-G and S-6-G in humans, studies were conducted to uncover mechanisms underlying their formation and elimination. In vitro metabolism study suggested that S-7-G was formed more easily but metabolized more slowly in human intestinal and hepatic microsomes. Efflux transporter study showed that S-6-G and S-7-G were good substrates of breast cancer resistance protein and multidrug resistance-associated protein (MRP) 2 and possible substrates of MRP3; however, there was no preference great enough to alter the S-7-G/S-6-G ratio in the blood. Among the major hepatic anion uptake transporters, organic anion-transporting polypeptide (OATP) 2B1 played a predominant role in the hepatic uptake of S-6-G and S-7-G and showed greater preference for S-7-G with higher affinity than S-6-G (K(m) values were 1.77 and 43.9 μM, respectively). Considering the low intrinsic permeability of S-6-G and S-7-G and the role of OATP2B1 in the hepatic clearance of such compounds, the selective hepatic uptake of S-7-G mediated by OATP2B1 is likely a key determinant for the much lower systemic exposure of S-7-G than S-6-G in humans.     

静吸复合麻醉对颅内手术患者麻醉用量及不良反应的影响

目的探讨静吸复合麻醉对颅内手术患者麻醉用量及不良反应的影响。方法选取我院2012年1月至2012年12月采取静吸复合麻醉方式行颅内手术患者60例,随机分成A、B、C三组,分别给予患者不同麻醉用量,观察不同麻醉用量麻醉效果和不良反应情况。结果 A组不良反应3例,发生率为15.0%,B组9例(30.0%),C组21例(70.0%);A组和B组麻醉效果差异明显(P<0.05),B组和C组麻醉效果比较无显著差异(P>0.05)。结论对于采取静吸复合麻醉方式行颅内手术患者,2～3μg/mL血浆靶浓度丙泊酚复合4～6ng/mL血浆靶浓度瑞芬太尼与3～5μg/ml丙泊酚复合6～8ng/mL血浆靶浓度瑞芬太尼麻醉效果与无明显差异,不良反应较少,值得进一步研究和临床推广应用。     

RP-HPLC法测定苦地丁及其复方制剂中紫堇灵的含量

采用反相高效液相色谱法测定苦地丁及其中药制剂感冒清热颗粒中紫堇灵的含量。色谱柱为APEX -ODS柱 ;流动相为甲醇 1 5mmol/L磷酸盐缓冲液 pH 6 70 ( 70∶30 ) ;流速为0 8mL/min ;检测波长为 2 89nm ;采用外标两点法进行定量。在紫堇灵为 6 9～ 1 1 0 4 μg/mL范围内线性关系良好 ,相关系数r=0 9999。方法精密度RSD分别为 1 5 %和 0 8% ,回收率为 97 3%和 97 5 %。方法适用于不同产地苦地丁及 3种不同剂型感冒清热颗粒中的紫堇灵含量。