1,2,4-Oxadiazole Topsentin Analogs with Antiproliferative Activity against Pancreatic Cancer Cells,Targeting GSK3β Kinase

A new series of topsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety, was efficiently synthesized. All derivatives were pre-screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. The five most potent compounds were further investigated in various pancreatic ductal adenocarcinoma (PDAC) cell lines, including SUIT-2, Capan-1, and Panc-1 cells, eliciting EC₅₀ values in the micromolar and sub-micromolar range, associated with significant reduction of cell migration. These remarkable results might be explained by the effects of these new topsentin analogues on epithelial-to-mesenchymal transition markers, including SNAIL-1/2 and metalloproteinase-9. Moreover, flow cytometric analysis after Annexin V-FITC and propidium iodide staining demonstrated that these derivatives enhanced apoptosis of PDAC cells. Keeping with these data, the PathScan intracellular signaling and ELISA array revealed cleavage of caspase-3 and PARP and a significant inhibition of GSK3β phosphorylation, suggesting this kinase as a potential downstream target of our novel compounds. This was further supported by a specific assay for the evaluation of GSK3β activity, showing IC₅₀ values for the most active compounds against this enzyme in the micromolar range.     

2-烷氨基-3-对氟苯基-5-甲基-6-(1H-1,2,4-三唑-1-基)-噻吩并[2,3-d]嘧啶-4(3H)-酮衍生物的合成及其杀菌活性

已见含氟类有机物具有杀菌能力的报道,将氟元素引入到噻吩并嘧啶酮的衍生物之中,考查其杀菌活性。通过Gewald反应生成噻吩,产物同PPh3、C2Cl6、Et3N作用得到膦亚胺,再用对氟苯基异氰酸酯与之作用得到碳二亚胺,之后与伯胺反应得到10种新的标题化合物,其结构经1HNMR、MS和元素分析表征。生物活性测试表明,此类衍生物对常见农作物部分菌体均表现出较大的抑制作用,其中以2-正庚氨基-3-对氟苯基-5-甲基-6-(1H-1,2,4-三唑-1-基)-噻吩并[2,3-d]嘧啶-4(3H)-酮活性最好,它对棉花枯萎菌的抑制率达90%。该系列物质相对不含氟元素的同种取代基的噻吩并嘧啶酮衍生物的杀菌活性有一定程度的提高。     

1,4-二取代-1,2,3-三氮唑的合成研究

以苄基氯(1a)、4-氯苄基氯(1b)、特戊酸氯甲酯(1c)为原料,通过叠氮取代和1,3-偶极环加成反应合成了三种含羟基的三氮唑衍生物1-苄基-4-羟甲基-1H-1,2,3-三氮唑(3a)、1-(4-氯-苄基)-4-羟甲基-1 H-1,2,3-三氮唑(3 b)、1-(特戊酸甲酯基)-4-羟甲基-1 H-1,2,3-三氮唑(3 c),实验应用FT-IR、1HNMR、13CNMR对产物的结构进行了表征,结果证实了合成路线的可行性,目标产物的收率分别为85.32%、90.26%、72.62%。     

Synthesis of perylene dianhydride-incorporated main chain polyimides and sequential structural transformation through a dipolar cycloaddition

Perylene dianhydride (PDA)-incorporated polyimides were prepared. The perylene unit in the polyimide was thermally converted to the corresponding N-heterocyclic polyarene unit through a Diels–Alder reaction. The monomer, 2,2-bis(3-amino-4-hydroxyphenyl) hexafluoropropane (6FAP), was modified via O-alkylation to improve the solubility of the polymer. 2-Ethylhexyl-attached 6FAP yielded a soluble copolyimide that contained ca. 70 mol% PDA using pyromellitic dianhydride. The perylene unit of the copolyimide transformed to a polyarene unit through the dipolar cycloaddition of 4-aryl-1,2,4-triazole-3,5-dione (TAD) and maleic anhydride. The perylene transformation of the polyimide occurred with 50% conversion with maleic anhydride and quantitatively with TAD. The PDA-copolymer exhibited a spectral blue-shift and red-shift by maleic anhydride and TAD, respectively.     

Syntheses and biological activities of novel diheterocyclic compounds containing 1,2,4‐triazolo[1,5‐a]pyrimidine and 1,3,4‐oxadiazole

In a search for novel agrochemicals with high activity and low toxicity, a series of diheterocyclic compounds containing 1,2,4‐triazolo[1,5‐a]pyrimidine and 1,3,4‐oxadiazole rings were designed and synthesized by a four‐step synthetic route starting from 2‐mercapto‐5,7‐dimethyl‐1,2,4‐triazolo[1,5‐a]pyrimidine. The structures of all the compounds synthesized were confirmed by ¹H NMR, mass spectroscopy and elemental analysis. The preliminary bioassay against Brassica campestris L and Echinochloa crusgalli Beavu indicated that the title compounds displayed herbicidal activity at the concentration of 100 ppm and that compounds 5a (R = CH₃), 5d (R = C₂H₅) and 5f (R = i‐Bu) were found to have particularly high activities. In addition, the results of an in vivo test at a concentration of 50 ppm showed that all the compounds prepared were highly active against Rhizoctonia slain, but not active against Fusarium oxysporum, Gibberella zeave and Phoma sparagi. A further in vivo test showed that compound 5j possessed better fungicidal activity against Rhizoctonia solani at a concentration of 200 ppm than Carbendazim and Validamycin A, which are well known for their fungicidal activity against Rhizoctonia solani. To our knowledge, this is the first report that 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives display fungicidal activity against Rhizoctonia solani. © 2001 Society of Chemical Industry     

Preparation of π-conjugated polymers consisting of 1-aminopyrrole and 4-amino-1,2,4-triazole units

π-Conjugated polymers based on 1-aminopyrrole and 4-amino-1,2,4-triazole were prepared. Pd-catalyzed organometallic polycondensation gave poly(arylene-ethynylene) (PAE)-type π-conjugated polymers consisting of BOC-protected 4-amino-1,2,4-triazole (Taz(BOC)) units (BOC = t-butoxycarbonyl). The number average molecular weights (M_n) were determined to be 5200–19,200 using GPC. An alternating copolymer of Taz(BOC) and bithiophene (Th–Th) units, P(Taz(BOC)-Th-Th)_n-Pd, with an M_n of 10,800 was also prepared by Pd-catalyzed organometallic polycondensation. (Taz(BOC)-Th-Th)_n-Pd showed a UV–Vis absorption peak at λ_max = 425 nm, which is reasonable for a π-conjugated five-membered ring polymer with a coplanar structure. The deprotection of the BOC group of the polymers proceeded at 200 °C; this BOC-deprotection was investigated using a model compound. The optical and electrochemical properties of the π-conjugated polymers are reported.     

Syntheses of 1,2,4-triazolo[4,3-c]pteridines. Potential substrates for xanthine oxidase

A synthetic route for the preparation of 9-phenyl-1,2,4-triazolo[4,3-c]pteridines 8 is described. Their reactivities towards xanthine oxidase from Arthrobacter M-4 are determined and compared with the pteridine derivatives 6-phenylpteridin-4[3H]-thione 5, 6-phenyl-4-thiomethylpteridine 6, 4-hydrazino-6-phenylpteridine 7, 3-N-methyl-6-phenylpteridin-4[3H]-thione 19, 4-amino-6-phenylpteridine 22 and 1-N-methyl-6-phenylpteridin-4[1H]-one 24, in order to inspect a possible influence of pyrimidine ring substitution pattern on their interaction with the bacterial enzyme. It has been suggested that a planar structure of the pteridine moiety and the substituents could be an important factor that so far has been overlooked when considering the enzyme activity. Some literature data are also discussed in view of revision of structure assignment of the compounds 12, 14, and 17. This revised version was published online in August 2006 with corrections to the Cover Date.     

4-氨基-1,2,4-三唑-NTO盐的晶体结构及性能

用X射线单晶衍射法测定了4-氨基-1,2,4-三唑(4-AT)与3-硝基-1,2,4-三唑-5-酮(NTO)制得的盐(AT)(NTO)的单晶结构。结果表明:该晶体为单斜晶系,属P21/c空间群,晶体学参数a=7.071(2),b=6.361(3),c=18.792(7);β=96.43(3)°;V=839.9(5)3;Z=4;Dc=1.694 g.cm-3;μ=0.145/mm;F(000)=440。在(AT)(NTO)晶体中,4-AT阳离子上所有的原子和NTO阴离子上所有的原子均在以各自三唑环为基础的一个平面上,两平面夹角为7.6°。由真空安定性(VST)、撞击感度、摩擦感度和静电火花感度试验所得的真空放气量、特性落高、爆炸概率、50%发火电压、50%发火能分别为0.28 mL.g-1(100℃/48 h),124.7 cm,0%,12.841 kV和2.515 J,表明,(AT)(NTO)对热是稳定的,对撞击、摩擦和静电火花是不敏感的。     

3-硝基-1,2,4-三唑-5-酮(NTO)废酸的循环利用

针对3-硝基-1,2,4-三唑-5-酮(NTO)硝化过程中产生大量废酸导致“三废”综合治理成本高的问题,通过向废酸中补加少量工业浓硝酸制成质量分数为70%的硝酸溶液作为硝化剂,硝化1,2,4-三唑-5-酮(TO),循环合成目标化合物NTO。采用红外光谱、核磁共振光谱、元素分析对其进行了结构表征。考察了硝化剂用量、反应时间、反应温度对产品的影响,优化了硝化反应条件,确定硝化的最佳反应条件为: n(TO)n(HNO₃)=16,反应温度60~65 ℃,反应时间1 h,纯度可达99.9%。废酸循环利用10次以上,平均收率82%,硝酸用量减少了67.6%。      

Theoretical study of an energetic material di-lH-1,3,4-triazole derivatives

Computations by density functional theory （DFT） method are performed on a series of di-lH-1,3,4-triazole derivatives with different sub- stituents and linkages. The heat of formation （HOF） is predicted by the designed isodesmic reactions. The predicted results reveal that -N3 and -N=N- groups are effective structural units for increasing the HOF values of the di-lH-1,3,4-triazole derivatives. The HOMO-LUMO gap is affected by the substituents and linkage groups. Detonation performance is evaluated using the Kamlet-Jacobs approach based on the calculated density and HOE The results indicate that -NO2, -NF2, -NH-, -NH-NH- and -N=N- groups are helpful for enhancing the detonation properties of di-lH-1,3,4-triazole derivatives. The bond dissociation energy and bond order of the weakest bonds are analyzed to investigate their stability. It is observed that the -CH2-, -CH2-CH2- and -CH=CH- groups are effective structural units for improving the stabilities of these derivatives. Considering the detonation performance and the stability, five compounds are screened as the potential candidates for high energy density materials.