Syntheses and Crystal Structures of Two New α-Aminophosphonate Derivatives Containing Thieno[2,3-d]pyrimidine

Two new a-aminophosphonate derivatives containing thieno[2,3-d]pyrimidine, diethyl（（（6-ethyl-2-methyl-4-oxothieno[2,3-d]pyrimidin-3 （4H）-yl）amino）（4-methoxyphenyl）methyl） phosphonate （1） and diethyl（（4-bromophenyl）（（6-ethyl-2-methyl-4-oxothieno[2,3-d]pyrimidin-3 （4//）-yl）amino）methyl）phosphonate （2）, have been synthesized by a facial phosphorylated reaction, and their structures were characterized by NMR, IR, HRMS and X-ray single-crystal diffraction. Compound 1 （C21H28N3O5PS, Mr = 465.49） belongs to the orthorhombic system, space group P212121, with a = 10.83653（16）, b = 12.04906（19）, c = 18.0061（3） A, V= 2351.06（6） A3, Z= 4, Dc= 1.315 g/cm3, p = 2.177 mm-1, F（000） = 984.0, the final R = 0.0389 and wR = 0.0985 for all data. Compound 2 （C20H25BrN304PS, Mr = 514.37） belongs to the orthorhombic system, space group P212121, with a = 10.9187（5）, b = 11.9522（4）, c = 17.7667（7） A, V= 2318.60（16） A3, Z = 4, Dc= 1.474 g/cm3,μ = 4.175 mm^-1, F（000） = 1056.0, the final R = 0.0367 and wR = 0.0946 for all data.

3D-QSAR and Docking Studies of Pyrido[2,3-d]pyrimidine Derivatives as Weel Inhibitors

In order to investigate the inhibiting mechanism and obtain some helpful information for designing functional inhibitors against Wee1, three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies have been performed on 45 pyrido[2,3-d] pyrimidine derivatives acting as Wee1 inhibitors. Two optimal 3D-QSAR models with significant statistical quality and satisfactory predictive ability were established, including the CoMFA model （q2=0.707, R2=0.964） and CoMSIA model （q2=0.645, R2=0.972）. The external validation indicated that both CoMFA and CoMSIA models were quite robust and had high predictive power with the predictive correlation coefficient values of 0.707 and 0.794, essen- 2 values of 0.792 and 0.826, the leave-one-out r2m（LOO） values of 0.781 and tim parameter rm2 0.809, r2（ all） values of 0.787 and 0.810, respectively. Moreover, the appropriate binding orientations and conformations of these compounds interacting with Wee1 were revealed by the docking studies. Based on the CoMFA and CoMSIA contour maps and docking analyses, several key structural requirements of these compounds responsible for inhibitory activity were identified as follows： simultaneously introducing high electropositive groups to the sub- stituents R1 and R5 may increase the activity, the substituent R2 should be smaller bulky and higher electronegative, moderate-size and strong electron-withdrawing groups for the substituent R3 is advantageous to the activity, but the substituent X should be medium-size and hydrophilic. These theoretical results help to understand the action mechanism and design novel potential Wee1 inhibitors.

Synthesis and Antitumor Activities of Novel 4-Morpholinothieno [3,2-d]pyrimidine Derivatives

A series of novel 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives was designed and synthesized.All of them were screened for their cytotoxic activities against large cell lung cancer（H460）,colon cancer （HT-29） and adenocarcinomic lung cancer（A549） cell lines in vitro.The pharmacological results indicate that most of the target compounds show moderate to significant activities.Especially compound 17 exhibits the most potent antitumor activities against H460,HT-29 and A549 cell lines with IC50 values of 0.57,0.45 and 1.45 μmol/L,respectively.

An Efficient Synthesis of Pyrido[2,3-<i>d</i>]pyrimidine Derivatives via One-Pot Three-Component Reaction in Aqueous Media

A series of pyrido[2,3-d]pyrimidines derivatives have been prepared by one-pot three-component reaction of 4(6)-aminouracil, malononitrile and aromatic aldehydes. This efficient synthesis was done under microwave irradiation conditions (method A) and also using catalytic amount of diammonium hydrogen phosphate [(NH4)2HPO4] (DAHP) in aqueous media (method B). This procedure has the advantages of good yields, easy work-up, and benign environmentally friendly character. Reaction could proceed via domino Knoevenagel-Michael-cyclization reactions.

Coupling Reaction of 4-Chloro-7-H-Pyrrolo[2,3-d]Pyrimidine with 2,3,5-Tri-O-Acetyl-b-D-Ribofuranosyl Chloride

Coupling reaction of 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine with 2,3,5-tri-O-acetyl -β-D-ribofuranosyl chloride under the basic condition was investigated. An abnormal coupling reaction, in which the heterocyclic base attacked at the carbon of 1,2-O-methylidene moiety instead of anomeric carbon of ribose was observed and the structure of products 5a, 5b were identified by NMR and X-Ray diffraction.

Synthesis and Crystal Structure of 7-Amino-2,3,4,5-tetrahydro-1,3-dimethyl-5-(2-nitrophenyl)-2,4-dioxo-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile DMF Solvate

The title compound 7-amino-2,3,4,5-tetrahydro-1,3-dimethyl-5-（2-nitrophenyl）- 2,4- dioxo-1H-pyrano[2,3-d] pyrirnidine-6-carbonitrile DMF solvate 1 （C19H20N6O6, Mr = 428.41） was synthesized and crystallized. The crystal belongs to the monoclinic system, space group P2 1/c with a = 11.383（2）, b = 13.372（2）, c = 13.673（2）A, β = 97.380（4）°, Z = 4, V = 2063.8（6）A^3, Dc = 1.379 g/cm^3,μ（MoKα） = 0.105 mm^-1, F（000） = 896, the final R = 0.0738 and wR = 0.1647 for 2964 observed reflections （I〉 2σ（I））. X-ray analysis reveals that the new pyran ring is coplanar, which is obviously different from those of other similar compounds. In addition, the unclassical hydrogen bonds of C-H…O and C-H…N are presented in the crystals except for the normal hydrogen bonds of N-H…O.

Synthesis and Crystal Structure of 2-Benzylamino-6-methyl-3-cyano-8- phenyl-5H-bispyrazolo[3,4-d,3',2'-b]pyrimidine

The title compound 2-benzylamino-6-methyl-3-cyano-8-phenyl-5H-bispyrazolo[3,4-d,3＇,2＇-b]pyrimidine crystallizes in orthorhombic, space group Pbca with a = 17.945（7）, b =10.862（4）, c = 19.481（7） A°, β = 90°, Z = 8, V = 1151.8（4） A°^3, Mr = 379.43, Dx = 1.327 g/cm^3,μ（MoKa） = 0.084 mm^-1, F（000） = 1584, the final R = 0.0513 and wR = 0.1128 for 2608 observed reflections （I 〉 2σ（I））. X-ray analysis reveals that the tricyclic portion of the molecule is effectively planar. In addition, there exist three intermolecular hydrogen bonds.

One-Pot Synthesis of Pyrido[2,3-d]pyrimidines Catalyzed by Bismuth(III)Triflate

Synthesis of uracil derivatives, such as pyrido[2,3-d]pyrimidine, is very important for the pharmaceutical industry due to their many biological activities. In our continuing efforts into the development of new synthetic strategies for the preparation of heterocyclic compounds in this study, we performed reflux reactions with the catalyst Bi(OTf)3 by using a one-pot, threecomponent method. The one-pot, three-component condensation of 6-amino-1,3-dimethyluracil, with arylaldehydes and malononitrile to generate a series of 7-aminopyrido[2,3-d]pyrimidine-6-carbonitrile derivatives has been carried out in the presence of bismuth triflate as a green and reusable catalyst.

Synthesis and Cytotoxicity of Novel Diaryl Ureas Containing 2-Amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl Group

A series of 2-amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl substituted diaryl urea derivatives was designed and synthesized. Their in vitro cytotoxicities against two cancer cell lines（Bel-7402 and A549） were evaluated by standard MTT assay. Six of tested compounds 6, 8, 10, 17, 21 and 22 exhibited more potent cytotoxicity superior to sorafenib. The structure activity relationship（SAR） study indicates that 2-amino-5,6,7,8-tetrahydropyrido- [4,3-d]pyrimidinyl group was an option for cytotoxic potency.

新型4-芳氧基吡啶并[3′,2′∶4,5]噻吩并[3,2-d]嘧啶衍生物的合成

2-氯-3-氰基吡啶与巯基乙酸乙酯经闭环反应制得3-氨基吡啶并[3,′2′∶4,5]噻吩-2-甲酸乙酯(1);1与甲酰胺第二次成环生成吡啶并[3,′2′∶4,5]噻吩并[3,2-d]嘧啶-4-酮(2);2经氯化后与取代苯酚反应合成了12个新型的4-芳氧基吡啶并[3,′2′∶4,5]噻吩并[3,2-d]嘧啶衍生物,其结构经1H NMR,13C NMR,IR和元素分析表征。

8-取代苯并呋喃[3,2-d]嘧啶类化合物的合成及其体外抗白血病细胞活性研究

设计合成14个8-硝基或8-氨基苯并呋喃[3,2-d]嘧啶类目标化合物(2a-g,3a-g),其结构经EI-MS、1H NMR和IR光谱确证。采用MTT法评价目标化合物对人白血病细胞K562体外增殖抑制活性,结果显示所合成化合物对K562细胞均具有一定的抑制作用,且8-氨基苯并呋喃[3,2-d]嘧啶类化合物的抗增殖活性均高于8-硝基苯并呋喃[3,2-d]嘧啶类化合物。

2-(2-吡啶)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶及其衍生物的合成

以N-叔丁氧羰基-4-哌啶酮为原料,设计合成了一种新型的2-(2-吡啶)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶及其3种衍生物,通过~1HNMR、LC-MS和HPLC确证了3种衍生物的结构。实验证明,所合成的3种衍生物能够高效抑制白血病K562细胞系的增殖,同时能够有效抑制卵巢癌HO-8910细胞的增殖。

Facile one-pot synthesis of pyrido[2,3-d]pyrimidine derivatives over ZrO_2 nanoparticles catalyst

An efficient synthesis of hexahydropyrido[2,3-d]pyrimidinetrione derivatives is achieved via tandem Knoevenagel-Michael addition of aromatic aldehydes,methylcyanoacetate and 4（6）-aminouracil in solvent-free conditions in the presence of 10 mol%of ZrO_2 nanoparticles（ZrO_2 NPs） as a heterogenous catalyst.The procedure is formed in high yields,short reaction time and an environmentally friendly specificity.

Synthesis and antitumor activity of α-aminophosphonate derivatives containing thieno[2,3-d]pyrimidines

Two series of thieno[2,3-d]pyrimidine derivatives were designed and synthesized, in which bioactive α-aminophosphonate subunits were introduced at the N3 position through an N-N bond connection. The in vitro cytotoxic activity of the novel compounds was tested against human esophageal carcinoma cells （EC109）, human hepatocarcinoma cells （HepG2）, human gastric carcinoma cells （MGC-803）, respectively, by the MTT method. The evaluation results revealed that compounds fimb, 6mf, 6mg, 6rid and 6nh exerted the most potent inhibition against HepG2, MGC-803 and EC109 cells, respectively. In particular, compound 6rag presented excellent inhibitory effect against HepG2 （91.2%） and MGC-803 （94.4%） cells.

A clean and efficient cyclocondensation to pyrido[2,3-d]pyrimidine derivatives in aqueous media

A series of pyrido[2,3-d]pyrimidine derivatives were easily constructed by cyclocondensation reactions of 6-aminouracils or 6- aminothiouracil withα,β-unsaturated carbonyl compounds（aldehyde,ketone and ester） possessing a leaving group on theβposition,in H_2O under reflux conditions.

吡啶并[3′,2′:4,5]噻吩并[3,2-d]嘧啶类衍生物的研究进展

吡啶并[3′,2′:4,5]噻吩并[3,2-d]嘧啶类衍生物具有独特的化学结构和多元杂环原子,类似于天然产物稠杂环生物碱具有广泛的生物活性和较低生物毒性,得到科研人员的关注。本文通过嘧啶环上2、3、4位和其他类型取代衍生物进行分类,改变不同位置的取代基团,具有多种生物活性,尤其在抗肿瘤方面能够显著提高抑制肿瘤细胞生长,概述了吡啶并[3′,2′:4,5]噻吩并[3,2-d]嘧啶类衍生物的合成方法和生物活性的研究,展望了稠杂环药物分子的设计方向和发展前景。

A novel and efficient synthesis of pyrazolo[3,4-d]pyrimidine derivatives and the study of their anti-bacterial activity

In this work 4-amino-6-aryl-2-phenyl pyrimidine-5-carbonitrile derivatives were synthesized through a one-pot, three-component reaction of an aldehyde, malononitrile and benzamidine hydrochloride, in the presence of magnetic nano Fe304 particles as a catalyst under solvent-free conditions. 3-Amino-6-aryl- 2-phenylpyrazolo[3,4-d]pyrimidine derivatives were prepared through an efficient and environmentally friendly reaction between 4-amino-6-aryl-2-phenylpyrimidine-5-carbonitrile derivatives and hydra- zine hvdrate and their antibacterial activity has been evaluated

Synthesis and antitumor activities of a new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives

A new series of 4,5-dihydro-lH-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized. The anti- tumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549 （human alveolar adenocarcinoma cell） and H460 （human lung cancer） by MTT assay. Most of the target compounds exhibited significant antitumor activities against A549 and H460 cancer cell lines. The most potent compound 4-（benzo[d][1,3]dioxol- 5-yl）-8,9-difluoro-2-（4-methylpiperazin-l-yl）-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine （CH05） （IC50 = 0.44 μM, 3.07 μM） was 2.0 and 8.4 times more active than gefitinib （IC50= 0.89 μM, 16.81 μM） against A549 and H460 cell lines, respectively.

Synthesis of N^2-arylaminopyrimidine-5-carbonitrile derivatives via S_NAr amination reaction

An efficient and high-yielding synthesis of N~2-arylaminopyrimidine-5-carbonitrile derivatives starting from arylamines and 2-methylthio-pyrimidine-5-carbonitriIe derivatives has been developed in the presence of cesium carbonate as basic reagent.This new protocol showed high chemical tolerance for a range of functional groups,and only the methylthio substituent on C2 of the pyrimidine ring was replaced with arylamine derivatives under the reaction conditions.

2-嘧啶氧基-N-芳基苄胺类化合物的ALS抑制活性的QSAR研究

乙酰乳酸合成酶(ALS)或乙酰羟酸合成酶(AHAS)存在于植物的生长过程中,很多此类酶的抑制剂实际上作为除草剂被广泛用于农业生产中.生物活性测试结果表明,2-嘧啶氧基-N-芳基苄胺类化合物对ALS具有一定的抑制活性.在此基础上,我们用两种三维定量构效关系(3D-QSAR)研究方法:比较分子立场分析(CoMFA)和比较分子相似性指数分析(CoMSIA),对该类化合物进行了3D-QSAR研究,并建立了相关的预测模型.其中,CoMFA模型的交叉验证相关系数(rcv2)为0.801,非交叉验证相关系数(r2)为0.947,标准偏差(s)为0.136,F值为133.371.CoMSIA模型的rcv2为0.744,r2为0.883,s为0.202,F值为56.472.计算结果表明,2-嘧啶氧基-N-芳基苄胺类化合物与ALS抑制活性有一定的相关性.获得的CoMFA和CoMSIA模型,将应用于指导该类化合物的设计.