4-芳基-6-芳氧甲基吗啉-3-酮衍生物的合成及其对A549肺癌细胞生长抑止活性的评价

A series of 4-aryl-6-aryloxymethylmorpholin-3-one derivatives were synthesized very efficiently from readily available starting compounds in two steps. Ring opening reactions of epoxides with aniline compounds on alumina gave corresponding β-aminoalcohols （3）. The resulting β-aminoalcohols were reacted with 2-chloroacetyl chloride to yield the desired 4-aryl-6-aryloxymethylmorpholin-3-one derivatives （5）. All compounds 5 were assayed for inhibitory activity against A549 lung cancer cell growth, and the inhibitory effect of the novel morpholin-3-ones on cell viability was dose-dependent.     

Synthesis and biological evaluation of a new series of histone deacetylases inhibitors

Histone deacetylases （HDACs） play an important role in tumorigenesis. Inhibition of HDACs is considered as a potent strategy for cancer therapy. Two lead compounds （ja and jb） were found to have activities against HDACs with IC50 at about 15 μmol/L. Then a new series of hydroximic acid derivatives were designed and synthesized based on them. The HDACs activity assay in vitro found that compounds J04 and ,109 are nearly as potent as the positive control drug Zolinza.     

Synthesis, Crystal Structure, Physical Properties, and Application of a Series of Functional Dibenzo[d,f][1,3]dioxepine Derivatives

The twisted aromatics, functional dibenzo[d,f][1,3]dioxepine derivatives were synthesized in high yields from reactions of 5,5＇-dibromo-2,2＇-biphenol with corresponding ketal or ketone compounds under acid catalysis. The structures of these compounds were characterized by ^1H NMR, elemental analysis, UV-Vis absorption spectrum and X-ray diffraction analysis. The conformation of O--C--O bridged biphenyl derivatives with varied substitute groups on 6,6＇-position was studied by X-ray crystallography and force-field simulation. The result of calculations by UNIVERSAL 1.02 force field in Cerius2 package（4.6） indicates that dibenzo[d,f][1,3]dioxepine derivatives show twisted conformations and the twisted angle between the phenyl rings is about 40°, which is accordant with the result from crystal structure determination, though the obtained angles in the crystal of dibenzo[d,f][1,3]dioxepine derivatives with the varied substitute groups on 6,6＇-position are shown to be slightly shifted to 40° owing to intermolecular interactions in crystal stacking. DSC studies exhibit that the substitute groups on 6,6＇-position can induce a large variation of endothermic peaks ranging from 80 to 135 ℃. The conjugated polymers based on dibenzo[d,f][1,3]dioxepine derivatives, which have ultraviolet emitting with a quantum efficiency of 10%, were obtained by Yamamoto coupling.     

Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the comparative molecular field analysis （CoMFA） for training set with significant statistical quality （R2=0.898） and predictive ability （q2=0.654） was established. The same model was further applied to predict pIC50 values of the compounds in test set, and the resulting predictive correlation coefficient R2（pred） reaches 0.816, further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very interesting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some important factors improving the activities of these compounds were discussed in detail and were summarized as follows： the substituents R3-R5 （on the phenyl ring） with higher electronegativity, the substituent R6 with higher eleetropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.     

Design and Synthesis of p/m-[p-（un）Substituted Phenylsulfonamido]phenyl β-Diketo Acids and Quinoxalone Derivatives

Diketo acid derivatives are potent and selective HIV-1 integrase inhibitors. To investigate the detailed synthesis of those derivatives, a series of p/m-[p-（un）substituted phenylsulfonamido]phenyl β-diketo acid derivatives have been designed and synthesized. The quinoxalone derivatives as the potential bioisosteres of the biologically labile β-diketoacid pharmacophores have also been synthesized from reactions of the corresponding diketo acids with o-phenylenediamine. The structures of all diketo acid （ester） and quinoxalone derivatives were confirmed by 1^H NMR, 13^C NMR, IR, HRMS and/or MS （ESI）. X-ray crystallographic analysis of 11b demonstrates a similar arrangement of the side chain of quinoxalone derivatives with the parent diketoacids due to the intramolecular hydrogen bond （O…H-N） and the sp^2 hybridization configuration of the two nitrogen atoms of the quinoxalone ring.     

Environmentally Benign Synthesis of 2-Pyrazolines and Cyclohexenones Incorporating Naphthalene Moiety and Their Antimicrobial Evaluation

We reported the environmental benign synthesis of chalcones,2-pyrazolines and cyclohexanones under microwave irradiation.Chalcones were obtained by the condensation of each of 2-hydroxyacetophenone derivatives with a-naphthaldehyde under microwave irradiation.The condensation reactions of each of synthesized chalcones with phenyl hydrazine under microwave irradiation in the presence of dry acetic acid as a cyclizing agent gave 2-pyrazolines.Also,the new cyclohexenone derivatives,valuable intermediates to synthesize fused heterocycles,have been prepared by the cyclocondensation of each of hydroxychalcones with ethyl acetoacetate.The structures of the synthesized compounds were elucidated by infrared（IR） spectrometry,nuclear magnetic resonance（NMR）,mass spectrometry（MS） and elmental analysis.The results indicate that unlike classical heating,microwave irradiation results in higher yields with shorter and cleaner reactions.The synthesized compounds were screened for antimicrobial activity against Staphylococcus aureus,Escherichia coli,Candida Albicans and Aspergillus niger.We clarified the effects of different substituents in the tested compounds on the obtaind antibacterial activities and antifungal activities.     

Interactions of Phenanthroline Compounds with i-Motif DNA

The interactions of each of three phenanthroline derivatives 1, 2 and 3 with the human telomeric/-motif DNA were investigated. The results suggest these compounds are potent binders. The compounds could stabilize the structure of i-motif DNA by π-π stacking. Moreover, the binding constants of the compounds with/-motif DNA were （2.71-8.12）×10^4 L·mol^-1, and the binding stoichiometry ratio was 1：1. CD studies reveal that the binding by phenanthroline comoounds perturbs the conformation of i-motif DNA.     

Synthesis and anti-HIV-1 activity of the conjugates of gossypol with oligopeptides and D-glucosamine

A series of novel gossypol derivatives were synthesized and screened for their in vitro anti-HIV- 1I activity. The results showed that replacing the aldehyde groups of gossypol with certain oligopeptides and Dglucosamine not only reduced the cytotoxicity of gossypol derivatives but also enhanced their antiviral activity against HIV-1. Interestingly, D-glucosamine derivative of gossypol that lacked the COONa group also exhibited the same potent anti-HIV-1 activity as oligopeptide derivatives with the COONa group. These compounds blocked the entry of HIV-1ⅢB into target cell. which was similar to T20. Furthermore, the molecular docking analysis rationalized their anti-HIV-1 activity. The results also implied that certain oligopeptides and D-glucosamine were important moities to prepare gossypol derivatives as HIV- 1 entry inhibitors besides certain amino acids.     

Design and synthesis of novel cytotoxic podophyllotoxin derivatives

<正>In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives,novel 4-Nand 4-C-substituted 4'-O-demethylepipodophyllotoxin derivatives were designed and synthesized.All the compounds were tested against A549 and MCF-7 tumor cells in vitro,and six compounds showed significant cytotoxicity.The most active compound 9f was superior to GL-331,and exhibited potent cytotoxicity with IC_(50) value at 10~(-7) mol/L level.     

A comparative QSAR analysis and molecular docking studies of phenyl piperidine derivatives as potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors

Depression is a critical mood disorder that affects millions of patients. Available therapeutic antidepressant agents are associated with several undesirable side effects. Recently, it has been shown that Neurokinin 1 receptor (NK₁R) antagonists can potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs). In this study, a series of phenyl piperidine derivatives as potent dual NK₁R antagonists/serotonin transporter (SERT) inhibitors were applied to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis–based multiple linear regression (FA-MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and NK₁R antagonism/SERT inhibitory of these compounds. The best multiple linear regression equation was obtained from GA-PLS and MLR for NK₁R and SERT, respectively. Based on the resulted model, an in silico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed for both targets. Molecular docking studies of these compounds on both targets were also conducted and encouraging results were acquired. There was a good correlation between QSAR and docking results. The results obtained from validated docking studies indicate that the important amino acids inside the active site of the cavity that are responsible for essential interactions are Glu33, Asp395 and Arg26 for SERT and Ala30, Lys7, Asp31, Phe5 and Tyr82 for NK₁R receptors.     

Synthesis of N1-phenethyl substituted indole derivatives as new melatoninergic agonists and antagonists

The potency of new indolic N1-phenethyl substituted melatoninergic ligands with and without methyl groups in the alpha and beta position of the alkanamidoethyl side chain was examined using the pigment aggregation response in a clonal line of Xenopus laevis melanophores. The non 5-OMe substituted compounds, 8a--e, are all weak antagonists while introduction of the 5-OMe group, 9a--e, increases both agonist and antagonist activity except for 9c (R=C3H7), which is only an agonist and 9e (R=c-C4H7), which is only an antagonist. Introduction of an alpha-methyl group into the 5-OMe derivatives, 14a-e, reduces the agonist potency while introduction of a beta-methyl group has only a small effect on either the agonist or antagonist potency. Double beta-methyl substitution of the 5-OMe derivatives, 20a--e, generally increases the agonist potential (20c, R=C3H7 is the most potent agonist of the compounds described) and decreases the antagonist potency, except for 20a (R=CH3), which is the most potent antagonist of this series of compounds.     

Synthesis and biological evaluation of a lipid A derivative that contains an aminogluconate moiety

A highly convergent strategy for the synthesis of several derivatives of the lipid A of Rhizobium sin-1 has been developed. The synthetic derivatives are 2-aminogluconate 3 and 2-aminogluconolactone 4, both of which lack C-3 acylation. These derivatives were obtained by the preparation of disaccharides in which the two amino groups and the C-3' hydroxy group could be modified individually with acyl or beta-hydroxy fatty acyl groups. Detailed NMR spectroscopy and MS analysis of 3 and 4 revealed that, even under neutral conditions, the two compounds equilibrate. The synthetic compounds lack the proinflammatory effects of Escherichia coli lipopolysaccharide (LPS), as indicated by an absence of tumor necrosis factor production. Although 3 and 4 were able to antagonize E. coli LPS, they were significantly less potent than the synthetic compound 2, which is acylated at C-3, and R. sin-1 LPS; these results indicate that the beta-hydroxy fatty acyl group at C-3 contributes to the antagonistic properties of R. sin-1 LPS. Based on a comparison of the biological responses of the synthetic lipid A derivatives with those of the R. sin-1 LPS and lipid A, the 3-deoxy-D-manno-octulosonic moieties appear to be important for the optimal antagonization of enteric LPS-induced cytokine production.     

Preparation and biological activity of 2-[4-(thiazol-2-yl)phenyl]propionic acid derivatives inhibiting cyclooxygenase.

A series of 2-[4-(thiazol-2-yl)phenyl]propionic acids substituted at various positions were prepared by the reaction of diethyl 2-methyl-2-(4-thiocarbamoylphenyl)malonates with alpha-bromoaldehyde diethyl acetals or alpha-haloketones followed by hydrolysis of esters. The inhibition of prostaglandin H synthetase (cyclooxygenase) was assayed by use of an enzyme preparation from guinea pig polymorphonuclear leukocytes. Examination of the structure-activity relationship of these compounds indicated that the substitution pattern with halogens at position 3 (R1) of the benzene ring and a methyl group in position 4 (R2) and/or 5 (R3) of the thiazole ring were favorable for inhibitory activity. The compounds bearing bulky alkyl or polar functional groups at the R2 position were weak inhibitors. The potent inhibitors of cyclooxygenase were tested for their ability to reduce carrageenin-induced inflammation of rat paws. These derivatives had strong anti-inflammatory activity based on their strong inhibition of cyclooxygenase, with some exceptions, including those with a thiomethyl group at R1.     

抗癌性吲哚喹唑啉衍生物3D-QSAR研究及其分子设计

吲哚喹唑啉衍生物是近年来发现的一类具有良好抗癌活性的化合物. 作者在最近报道的二维定量构效关系(2D-QSAR)的基础上, 采用比较分子力场方法(CoMFA)进一步对该系列化合物进行三维定量构效关系(3D-QSAR)研究, 建立了3D-QSAR的CoMFA模型, 其非交叉验证相关系数r2=0.986, 标准偏差SD=0.084, 统计方差比F=114.6, 交叉验证相关系数q2=0.695, 表明该模型合理、可信, 并具有良好的预测能力. 研究结果表明: (1) 取代基R1的部位上静电效应起主要作用, 并且确保取代基R1的第一个原子具有较大的净正电荷, 对提高化合物的抗癌活性十分重要. 这与2D-QSAR研究结果相一致. (2) 取代基R2的部位上立体效应起主要作用, R2的体积大小要适中. 应用这些规律进行了分子设计, 在理论上获得了一些具有较高抗癌活性的新的吲哚喹唑啉衍生物, 并期待实验证实. 该QSAR的研究结果可为实验工作者合成新药提供理论参考.     

Orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activity of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives containing a tertiary amine moiety

The search for orally active CCR5 antagonists was performed by chemical modification of the 1-benzothiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compounds containing a tertiary amine moiety. Replacement of methyl group with a 2-(C(2-4) alkoxy)ethoxy group at the 4-position on the 7-phenyl group of the 1-benzothiepine ring resulted in both enhanced activity and significant improvement in the pharmacokinetic properties upon oral administration in rats. Introduction of C(2-4) alkyl, phenyl or (hetero)arylmethyl groups as the 1-substituent on the 1-benzazepine ring together with the 2-(butoxy)ethoxy group led to further increase of activity. Among the 1-benzazepine derivatives, the isobutyl (6i), benzyl (6o) or 1-methylpyrazol-4-ylmethyl (6s) compounds were found to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activity (IC(50)=2.7 nM) and inhibitory effect (IC(50)=1.2 nM) on membrane fusion, together with good pharmacokinetic properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives and their biological activity are described.     

苯并嗪酮衍生物的3D-QSAR分析

苯并嗪酮衍生物是近年来发现的一类抗血小板聚集化合物, 在前人研究的基础上利用比较分子场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)对23个苯并嗪酮衍生物进行了三维定量构效关系(3D-QSAR)研究. 其中CoMFA模型交叉验证系数Q2=0.703, 回归系数R2=0.994, 计算值与实验值的平均方差SEE=0.053, 统计方差比F=184.773; CoMSIA模型Q2=0.847, R2=0.992, SEE=0.058, F=171.670. 两种方法得到的模型都具有较好的预测能力. 结果表明, 标题化合物中8-位取代基R1静电效应起主要作用; 2-位取代基R2立体效应占主导作用, 但官能团大小要适中. 根据研究结果设计了六种活性较高的化合物.     

Antihyperglycemic agents from Ammannia multiflora

The serial chromatographic separation of chloroform and n-butanol fractions of Ammannia multiflora resulted in the isolation and characterization of 4-hydroxy-alpha-tetralone (1) and 3,3'-(2R,5R)-tetrahydrofuran-2,5-diyldiphenol (ammaniol, 2). Compound 1 was chemically modified into six semi-synthetic acyl and aryl derivatives (1A - 1F). The isolated compounds 1 and 2 along with semi-synthetic derivatives 1A - 1F were evaluated for in vitro antihyperglycemic activity employing 2-deoxyglucose uptake by L-6 rat muscle cell lines. The results indicated that both the isolates, as well as derivatives (1A - 1F), have the property to stimulate glucose uptake. Ammaniol (2) increased glucose uptake significantly (64.8%), while one of the aryl derivatives of 1, 4-O-(3,4,5-trimethoxybenzoyl)-alpha-tetralone (1D), showed potent antihyperglycemic activity and increased glucose uptake by 94.6%, even more than rosiglitazone (88.8%). Further, since 1D possesses better antihyperglycemic activity than rosiglitazone (standard), this might be a new safer antidiabetic drug of herbal origin.     

Novel malonamide derivatives as alpha v beta 3 antagonists. Syntheses and evaluation of 3-(3-indolin-1-yl-3-oxopropanoyl)aminopropanoic acids on vitronectin interaction with alpha v beta 3.

In attempt to find novel integrin alphavbeta3 antagonists, we selected SC65811 and its guanidine analogue (1) as lead compounds. Modification of the glycine part of SC65811 led to a new series of malonamide derivatives that exhibited alphavbeta3 inhibitory activity. Among them, (R,S)-3-[3-[6-(3-benzylureido)indolin-1-yl]-3-oxopropanoylamino]-3- (pyridin-3-yl)propanoic acid (43a) showed not only potent activity with an IC50 value of 3.0 nM but also good selectivity for alphavbeta3 relative to alphaIIbbeta3, alpha5beta1, and alphavbeta5 with IC50 values of 19,000, 11,000, and 14 nM, respectively. Furthermore, optimization of 43a led to the most potent alphavbeta3 antagonist, (R,S)-3-(3-[6-[(4,5-dihydro-1H-imidazol-2-yl)amino]indolin-1-yl]-3-oxopropanoylamino)-3-(quinolin-3-yl)propanoic acid (431) with an IC50 value of 0.42 nM. The synthesis and the structure-activity relationships of these malonamide derivatives are presented.