2-酰胺-6-乙酰基吡啶类化合物的微波合成及其晶体结构

2,6-二甲基吡啶经氧化、酯化、Claisen酯缩合后制得新型化合物2-乙酯基-6-乙酰基吡啶(4), 用其作为前驱体, 与一系列小分子脂肪胺: 甲胺、乙胺、乙二胺在微波条件下生成3个吡啶酰胺化合物5, 6, 7. 通过元素分析, ¹H NMR, IR和MS对这些化合物进行了表征. 对6-乙酰基-N-甲基吡啶-2-甲酰胺(5)的X射线晶体衍射研究表明: 其属于正交晶系, Pca2(1)空间群, 晶胞参数a＝2.2784(2) nm, b＝0.4350(4) nm, c＝0.9267(3) nm; α＝β＝γ＝90°; D_c＝1.288 Mg•m^－3, V＝0.91856(14) nm³. 实验还发现: 2-乙酯基-6-乙酰基吡啶与脂肪胺及芳香胺缩合时会发生两类不同的反应, 小分子脂肪胺选择与酯基发生胺解反应, 而芳香胺则率先在乙酰基上发生席夫碱缩合. 对这两类有趣的反应机理进行了深入探讨.     

超声辐射下N-苄基-α,α-二苯基-2-吡咯烷甲醇衍生物的制备及其杀虫活性测定

在无水无氧、超声辐射下, N-取代苄基脯氨酸苄基酯与取代苯基溴化镁反应合成了7个未见文献报道的N-苄 基-α,α-二苯基-2-吡咯烷甲醇衍生物, 其结构经IR, ¹H NMR和元素分析测试确证, 并且初步生物活性测定结果表明目标化合物均有较好的杀虫活性.     

N-{2-氯-5-[3-甲基-2,6-二氧-4-三氟甲基-2,3-二氢嘧啶-1(6H)-基]苯基}酰胺类化合物的合成及除草活性

为了寻找高效、安全的除草活性化合物, 合成了12个全新的N-{2-氯-5-[3-甲基-2,6-二氧-4-三氟甲基-2,3-二氢嘧啶-1(6H)-基]苯基}酰胺类化合物, 其化学结构经IR, ¹H NMR, LC/MS和元素分析确证. 初步生物活性测定结果表明, 该类化合物具有一定的除草活性, 如7a, 7b, 7c, 7g, 7h, 7i, 7k和7l在有效成分75 g/hm²剂量下, 茎叶处理对苘麻(Abutilon theophrasti)、刺苋(Amaranthus spinosus)等阔叶杂草具有良好的除草活性, 其抑制率达100%.     

具有除草活性的吡唑啉并四嗪酮衍生物的设计、合成与定量构效关系的研究

设计合成了一系列未见文献报道的4-乙氧羰基-1,7-二氢-1-取代苯基-5-(未)取代吡唑啉[5,1-d][1,2,3,5]四嗪-7-酮衍生物, 其结构均经过¹H NMR、IR和元素分析表征. 生测结果显示, 与已报道的化合物相比, 它们表现出较好的除草活性. 定量的结构与活性关系研究表明, 它们的除草活性与取代基的立体效应参数和疏水性参数呈现很好的相关性, 相关系数r大于0.8. 当作用对象为油菜时, 化合物的活性可能主要与取代基R¹的摩尔分子折射和取代基R²的疏水性参数有关. 当取代基R¹的摩尔分子折射参数为1.452时, 相应化合物可能具有对油菜最高的除草活性; 当作用对象为稗草时, 化合物的活性主要与取代基R²疏水性参数和Taft (Es)参数有关.     

[1-芳基甲羰基-2-(1,2,4-三唑-1-基)]乙基-N,N-二烷基二硫代氨基甲酸酯衍生物的合成、结构表征及生物活性研究

以芳香基三唑类杀菌剂三唑酮为先导物设计并合成了5个含N,N-二烷基二硫代氨基甲酸酯的芳香三唑类化合物, 通过元素分析、红外光谱、核磁共振氢谱和质谱对其结构进行了表征. 用X射线单晶衍射测定了[α-(4-甲氧基苯甲酰基)-2-(1,2,4-三唑-1-基)]乙基-N,N-二甲基二硫代氨基甲酸酯的晶体结构, 晶体属于三斜晶系, 空间群, 晶胞参数为: a＝0.73482(15) nm, b＝1.1051(2) nm, c＝1.1209(2) nm, α＝90.32(3)°, β＝101.97(3)°, γ＝105.13(3)°, V＝0.8578(3) nm³, Z＝2, D_c＝1.357 g/cm³, F(000)＝368, µ＝0.324 mm^－1. 生物测试结果显示这5种有机化合物都具有杀菌性和植物生长调节活性     

N-(安替比林-4-基)-N'-取代芳甲酰基硫脲的合成及其生物活性

合成了12个含安替比林基的取代芳甲酰基硫脲类化合物, 用¹H NMR, IR和元素分析确证了它们的结构, 并进行了室内生物活性测试. 生测实验证明部分酰基硫脲类化合物, 比如N-(安替比林-4-基)-N'-m(或o)-甲苯甲酰基硫脲, N-(安替比林-4-基)-N-o-硝基苯甲酰基硫脲, N-(安替比林-4-基)-N'-m(或p)-氯苯甲酰基硫脲, 具有一定的细胞分裂素活性.     

1,3-偶极环加成合成新型3a,6a-二氢-4,6-二氧代吡咯啉并[3,4-d]吡唑类衍生物

α-氯代-4-氧代-4H-1-苯并吡喃-3-甲醛芳腙与N-取代苯基-马来酰亚胺在三乙胺作用下通过1,3-偶极环加成合成了一系列含3-(4-氧代-4H-1-苯并吡喃-3-基)-3a,6a-二氢-4,6-二氧代吡咯啉并[3,4-d]吡唑类衍生物. 化合物结构经元素分析, IR, ¹H NMR及MS确证.     

取代吡唑-5-酰基杂环衍生物的合成、结构与生物活性

为了寻求新的含吡唑双杂环先导化合物. 用4-取代-1-甲基-3-乙基-5-吡唑甲酰氯与2-噻唑烷酮、2-噻唑硫酮、2-噁唑烷酮等含氮杂环反应得到了12个含吡唑环的双杂环化合物. 化合物结构用IR, ¹H NMR, MS和元素分析进行了表征. 并用X射线单晶衍射法测定了化合物3-(1-甲基-3-乙基-4-硝基-5-吡唑甲酰基)-噁唑烷-2-酮(3k)的晶体结构. 晶体为单斜晶系, P2₁/n (#14)空间群, a＝1.52175(3) nm, b＝0.52970(1) nm, c＝1.58185(3) nm, β＝104.893(4), V＝1.2323(4) nm³, Z＝4, D_c＝1.45 g/cm³, F(000)＝560.00, R₁＝0.064, wR₂＝0.193. 初步生物活性实验结果表明, 在25 mg/L浓度下, 3-(1-甲基-3-乙基-4-硝基-5-吡唑甲酰基)-噻唑烷-2-酮(3c), 3-(1-甲基-3-乙基-4-硝基-5-吡唑甲酰基)-噻唑烷-2-硫酮(3g)对水稻稻瘟病菌(Pyricularia oryzae)的抑制活性达到40%. 在500 mg/L浓度下, 3-(1-甲基-3-乙基-4-溴-5-吡唑甲酰基)-噻唑烷-2-酮(3d), 3-(1-甲基-3-乙基-4-溴-5-吡唑甲酰基)-噁唑烷-2-酮(3l)对稻黑尾叶蝉(Nephotettix cinc-ticeps)的抑制活性达到53.37%.     

氨基糖衍生物二丁基锡配合物的合成、结构表征和生物活性

分别由2-[(2Z)-3-羧基-1-氧代-2-丙烯基]氨基-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖(1a), 2-[(2-羧基苯甲酰基)氨基]-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖(2a)和氧化二正丁基锡反应合成了两个新化合物双-{2-[(2Z)-3-羧基-1-氧代-2-丙烯基]氨基-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖}-二正丁基锡酯(1)和双-{2-[(2-羧基苯甲酰基)氨基]-2-脱氧-1,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖}-二正丁基锡酯(2), 并经红外光谱、核磁共振(¹H, ¹³C NMR)、质谱初步确定了其结构. 体外抗肿瘤活性结果表明, 化合物1对人肺癌细胞株A-549和人肝癌细胞株BEL-7402的细胞毒活性显示为强效; 而对小鼠白血病细胞株P388和人白血病细胞株HL-60的细胞毒活性为弱效. 化合物2对肿瘤细胞株HL-60, A-549和BEL-7402具有强效的细胞毒活性; 而对肿瘤细胞株P388的作用则为弱效. 克隆基因分析表明化合物1和2在3.82×10^－6 和 3.02×10^－6 mol/L均具有造血细胞毒性.     

一种多芳基取代三唑及其镉(Ⅱ)配合物的合成、结构与性质研究

合成了配体3-(2-吡啶基)-4-(对甲氧苯基)-5-(2-噻吩基)-1,2,4-三唑(L),通过IR、¹H NMR、¹³C NMR、MS、元素分析、紫外和荧光等测定对其进行表征。利用配体L与CdI₂反应,合成出一种镉(Ⅱ)的配合物[CdLI₂]₂,其结构由单晶X衍射结构分析、红外、紫外、元素分析表征。该晶体属于单斜晶系,空间群为P2₁/c。晶体结构表明：每个镉离子与3个碘离子和2个氮原子配位,形成了变形的四方锥几何构型,配合物是以Cd₂I₂四边形中心内环为对称中心而形成的二聚体。采用滤纸片法对E. Coli、P. Aeruginosa和S. Aureus进行抗菌活性试验,配体和配合物均表现一定的抑菌活性。     

Synthesis and Antitumor Activity of 7-Substituted Derivatives of Homocamptothecin

Camptotecin is the parent of an important class of anticancer agents which, can selectively poison the ubiquitous nuclear enzyme topoisomerase. Water soluble camptothecin analogues such as topotecan and irinotecan are already approved for clinical uses in…     

Chiral capillary electrophoretic determination of the enantiomeric purity of homocamptothecin derivatives, promising antitumor topoisomerase I inhibitors, using highly sulfated CDs and fluorescence detection

EKC methods for the enantiomeric resolution of homocamptothecin derivatives, potent anticancer agents targeting DNA topoisomerase I selected for clinical trials, were developed using highly sulfated beta-CD as chiral selectors at acidic pH. Optimal electrophoretic conditions, with migration times under 15 min, were as follows: for the neutral homocamptothecin analog 1, a BGE of 75 mM phosphate buffer pH 2.5 (H(3)PO(4) + triethanolamine)/ACN - 95/5 v/v, with 7.5% w/v highly S-beta-CD, an applied field of 0.2 kV/cm and a fused capillary temperature control of 30 +/- 0.1 degrees C (typical current approximately 175 microA); for the cationic homocamptothecin 2, a BGE of 25 mM phosphate buffer pH 2.5 (H(3)PO(4) + TEA)/ACN - 90/10 v/v, with 2.5% w/v highly S-beta-CD, an applied field of 0.15 kV/cm and a fused capillary temperature control of 25 +/- 0.1 degrees C (typical current approximately 45 muA), and both are validated. The best results in terms of LOQ were obtained by EC with fluorescence detection: 10 ng/mL and 20 ng/mL for 1 and 2, respectively (LOQ divided by 150 for 1 and 5 for 2 with respect to UV), thus making this method particularly convenient for enantiomeric purity determination of galenic forms. UV detection appears to be an alternative to fluorescence for the analysis of the main component either for the control of galenic forms or for therapeutic adaptation. Moreover, this method exhibits better performances than HPLC.     

Assessment of the complexation degree of camptothecin derivatives and cyclodextrins using spectroscopic and separative methodologies

The complexation of camptothecin and homocamptothecin derivatives, topoisomerase I inhibitors, with two cyclodextrins (CDs) of pharmaceutical interest (native and hydroxypropylated β-CD) was studied at pH 3.5 and 6. In a first step, the affinity order of the six compounds studied for the β-CD and HP-β-CD was evaluated in HPLC using immobilized stationary phases [Cyclobond I 2000 (β-CD) and Cyclobond I 2000 RSP (HP-β-CD)]. In a second step, the apparent binding constants of the 12 complexes studied were determined at both pH by HPLC using Scott’s method with CD as a chiral additive. The 1:1 stoichiometry of the complex formed between HP-β-CD and the homocamptothecin derivative elomotecan (R)-6 was established by fluorescence spectroscopy using the continuous variation method developed by Job and ESI-MS. Complementary investigations were achieved for topotecan (S)-3 and elomotecan (R)-6 using CE. Further studies provided similar conclusions concerning affinity of all the derivatives studied for both CDs: that is, a slightly larger affinity was observed for HP-β-CD with respect to β-CD, except for (S)-3. For (S)-3, this affinity increase with pH, in the range studied.     

Synthesis and antitumor activity of novel 10-amino acids ester homocamptothecin analogues

Nine racemic homocamptothecin derivatives were synthesized and in vitro antitumor activities were evaluated by standard MTT method. The results showed that some of the compound had higher antitumor activity than iritecan.     

一类高喜树碱化合物的新型合成方法

本文以溴乙酸叔丁酯与9-羟基喜树碱反应,引入了羧酸官能团,能很方便地合成一系列高喜树碱酰胺化合物。本路线摈弃了磷酸酯等保护基团,路线简洁,收率提高,羧酸官能团起到了提高喜树碱溶解度的作用,便于后面反应的进行和产物纯化。     

拓扑异构酶Ⅰ抑制剂高喜树碱类化合物的三维定量构效关系研究

针对拓扑异构酶Ⅰ抑制剂高喜树碱类化合物,采用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)的方法对其进行三维定量构效关系的研究.构建CoMFA模型其q2=0.706,最佳主成分数n=6,非交叉验证系数r2=0.966,标准差S=0.277,F=117.613,立体场和静电场的贡献值分别为0.62和0.38.构建CoMSIA模型其q2=0.696,最佳主成分数n=7,非交叉验证系数r2=0.956,标准差S=0.320,F=74.374,其疏水场和立体场的贡献分别为0.75和0.25.结果显示疏水场和立体场对化合物的活性有较大影响.     

Synthetic approaches to homocamptothecin antitumor agents

Homocamptothecins are proving to be an especially interesting class of anti-cancer agents because they resemble standard camptothecins in cytotoxicity but have very different pharmacodyanamic properties. This review summarizes synthetic approaches to the parent homocamptothecin and its analogs. Three powerful and general routes—the Lavergne–Comins route, the cascade radical annulation route, and the Friedlander route—have been put into place to make homocamptothecins. These routes are compared and contrasted. Together, they have driven the SAR, preclinical, and clinical development of this class of anti-cancer agents.     

Practical formal total syntheses of the homocamptothecin derivative and anticancer agent diflomotecan via asymmetric acetate aldol additions to pyridine ketone substrates

Two practical, efficient, and scalable asymmetric routes to DE ring fragment 7, a key building block in the synthesis of the homocamptothecin derivative diflomotecan 4, are described. The "acetal route" starts from 2-chloro-4-cyanopyridine 8 and represents an enantioselective and optimized modification of the original racemic discovery chemistry synthesis. The inefficient optical resolution procedure was replaced by an efficient asymmetric acetate aldol addition (dr 87:13) to a ketone substrate as the key step generating the (R)-configured quaternary stereocenter with high stereoselectivity. 7 was finally obtained in 8.9% overall yield (er 99.95:0.05) over nine steps, avoiding chromatographic purifications and comparing favorably with the initial procedure. In the related "amide route" starting from 2-chloroisonicotinic acid 41, a secondary amide directing group was used to facilitate the ortho lithiation of the pyridine 3-position. The key step of this protocol again consists of a practical asymmetric acetate aldol addition (dr = 87:13). The DE ring building block 7 was thus obtained in 11.1% overall yield (er > 99.95:0.05) over nine steps requiring only one chromatographic purification.     

Chiral Resolution of Enantiomers of Homocamptothecin Derivatives, Antitumor Topoisomerase I Inhibitors, Using High Performance Liquid Chromatography on Polysaccharide-Based Chiral Stationary Phases

Analytical HPLC methods using derivatized cellulose and amylose chiral stationary phases were developed for the separation of the enantiomers of homocamptothecin (hCPT) derivatives which constitute a promising series of potent anticancer agents targeting DNA topoisomerase I. The resolutions were performed using a normal phase methodology with two silica-based celluloses tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H) and tris-methylbenzoate (Chiralcel OJ) or two amyloses tris-3,5-dimethylphenylcarbamate (Chiralpak AD) and tris-(S)-1-phenylethylcarbamate (Chiralpak AS). The mobile phase and the chiral stationary phase were varied to achieve the best resolution. Different types and concentration of aliphatic alcohols in the mobile phase were also tested along with the temperature dependence. An optimal baseline separation (Rs > 1.5) was readily obtained in most cases. The different columns gave complementary results in term of resolution. The limits of detection and quantification were between 0.08–0.40 M and 0.24–1.80 M, respectively and the enantiomeric purity was superior to 99.9%.     

Sensitive flow-injection amperometric detection of iodide using Mn3+ and As3+.

A rapid, selective, and sensitive kinetic flow-injection method for iodide content determination with amperometric detection on a platinum electrode was developed. The method is based on the catalytic effect of iodide on the Mn3+ reaction with As3+ in the presence of sulfuric acid. The calibration curve was linear in the concentration range from 5.0 x 10(-7) to 1.0 x 10(-4) mol/L iodide. The limit of detection (LOD) was found to be 5.0 x 10(-9) mol/L iodide. The relative standard deviations (RSD) were 1.68% and 3.03% for 1.0 x 10(-3) mol/L standard and 1.0 x 10(-6) mol/L iodide solution (n = 6), respectively. The method has been successfully applied for determination of iodide in waters, table salts, fodder, organic substances and human blood sera. The results were compared with those obtained by a standard AOAC (Association of Official Analytical Chemists) method, as well as with those obtained by a kinetic spectrophotometric procedure for determination of iodide.