Synthesis and anticancer activity of novel chiral D-glucose derived bis-imidazoles and their analogs.

A series of novel D-glucose derived bis-imidazoles and their analogs, which possess potential in bioorganic and supramolecular chemistry, were designed and synthesized from methyl alpha-D-glucoside through protection, bis-bromination, N-alkylation and deprotection. All new compounds were characterized by HRMS, 1H, 13C and DEPT NMR spectroscopy as well as elemental analysis. The 1H-(1)H and 1H-(13)C 2D NMR spectra for some compounds were also recorded. Some regular features of 13C and 1H NMR spectra were summarized. The anticancer activity of some compounds was evaluated.     

Toward the development of chemoprevention agents (III): synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes

A new series of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes were designed and synthesized. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model. Sixteen of these new compounds exhibited comparable or better anti-inflammatory activities than aspirin suggesting that they can be further developed as potential anti-inflammatory drug leads. In addition, treatment with these anti-inflammatory agents did not prolong tail bleeding time in mice. The structure/activity relationships were also analyzed among these compounds. Considering their good efficacy and safety profiles, some 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes are worthy to be explored further in assessing the possible link between anti-inflammation and cancer prevention.     

Synthesis and antimycobacterial activity of new quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives

As a continuation of our research and with the aim of obtaining new antituberculosis agents which can improve the current chemotherapeutic antituberculosis treatments, new series of quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis strain H(37)Rv, using the radiometric BACTEC 460-TB methodology. Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line. The results indicate that some compounds exhibited a good antituberculosis activity and the arylcarboxamide analogues 3, 8, and 9 were the most active compounds (EC(90)/MIC1). Also, the cytotoxic effects indicate that these compounds have a good Selectivity Index (SI).     

Sulfur,selenium and tellurium pseudopeptides: Synthesis and biological evaluation

A new series of sulfur, selenium and tellurium peptidomimetic compounds was prepared employing the Passerini and Ugi isocyanide based multicomponent reactions (IMCRs). These reactions were clearly superior to conventional methods traditionally used for organoselenium and organotellurium synthesis, such as classical nucleophilic substitution and coupling methods. From the biological point of view, these compounds are of considerable interest because of suspected anticancer and antimicrobial activities. While the sulfur and selenium containing compounds generally did not show either anticancer or antimicrobial activities, their tellurium based counterparts frequently exhibited antimicrobial activity and were also cytotoxic. Some of the compounds synthesized even showed selective activity against certain cancer cells in cell culture. These compounds induced a cell cycle delay in the G0/G1 phase. At closer inspection, the ER and the actin cytoskeleton appeared to be the primary cellular targets of these tellurium compounds, in line with some of our previous studies. As most of these peptidomimetic compounds also comply with Lipinski’s Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations.     

Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer’s disease

This paper describes the synthesis and evaluation of new dihydropyrimidinone (DHPM)-derived selenoesters as potential multi-targeted agents for the treatment of Alzheimer’s disease. A series of DHPM-derived selenoesters were obtained with high structural diversity through a short and modular synthetic route. The antioxidant activity was evaluated by TBARS and iron chelation assays. These compounds were also evaluated as acetylcholinesterase inhibitors (AChEi). The compounds demonstrated good antioxidant activity, since they presented excellent lipid peroxidation inhibition and good iron chelation activity. In addition, they showed acetylcholinesterase inhibition activity and some of them presented activity superior to that of the standard drug galantamine. The in silico predictions showed that the compound 1h may present a good pharmacokinetic profile. Therefore, the series of DHPM-derived selenoesters described herein displayed good potential for the development of antioxidant and anticholinesterasic agents in the search for new multi-targeted therapeutics for the treatment of Alzheimer’s disease.     

Synthesis and evaluation of novel aromatic substrates and competitive inhibitors of GABA aminotransferase

The design, synthesis, and evaluation of novel gamma-aminobutyric acid aminotransferase (GABA-AT) inhibitors and inactivators can lead to the discovery of new GABA-related therapeutics. To this end, a series of aromatic amino acid compounds was synthesized to aid in the design of new inhibitors and inactivators of GABA-AT. All compounds were tested as competitive inhibitors of GABA-AT. The amino acids with benzylic amines were also tested as substrates for GABA-AT. It was found that these compounds were all poor competitive inhibitors of GABA-AT, but some were substrates of the enzyme, suggesting their utility as scaffolds for potential GABA-AT mechanism-based inactivators. Computer modeling was used to rationalize the substrate activity of the various compounds.     

Design, synthesis, and antitumor activity of new bis-aminomethylnaphthalenes

A new series of bis-aminomethylnaphthalenes were synthesized in satisfactory overall yield, through a simple synthetic strategy using reductive amination. The DNA binding properties of these compounds have been examined and compared to those of reference drugs using an UV spectroscopy method. The compounds were evaluated for their in vitro anticancer activity and some of them were studied in vivo. Compound 15 exhibited remarkable antitumor activity and represents a novel template for anticancer chemotherapy and can serve as a new lead compound.     

Synthesis, antiproliferative and antifungal activities of some 2-(2,4-dihydroxyphenyl)-4H-3,1-benzothiazines

A new method for the synthesis of 4H-3,1-benzothiazine skeleton is described. The compounds were obtained by the reaction of sulfinylbis(2,4-dihydroxythiobenzoyl) with o-substituted anilines bearing an activated methylene group (-CH2OH, -CH2NR1R2), o-aminobenzanilides or 2-aminobenzophenones. The reaction proceeded through thiobenzanilide intermediates, which were converted to the 4H-3,1-benzothiazine fused ring by an endocyclization process. The compounds were tested for their antiproliferative properties against the cells of a human breast cancer T47D line. The activity of some compounds was comparable to that of cisplatin, studied as a control. A strong antifungal effect against the strains of moulds, yeasts and dermatophytes was also found.     

Isolation and synthesis of analgesic and anti-inflammatory compounds from Ochna squarrosa L

Two new furanoflavonoids (1, 2), one new chalcone dimer (3) along with six known compounds, chrysophanol, 5-O-methyl squarrosin, 5-methoxy furano[4',5',6,7]flavone, calodenone, lophirone A and lophirone H were isolated from the ethyl acetate-soluble fraction of methanol extract of root bark of Ochna squarrosa. Chrysophanol, calodenone, lophirone A and lophirone H were isolated from this plant for the first time. The structures of all the isolated compounds were confirmed by 1D and 2D spectroscopic data. These compounds were tested for analgesic and anti-inflammatory activity. All the new compounds showed good analgesic and anti-inflammatory activity. A simple and facile method for the cleavage of benzyl ethers using I(2) in trigol is also reported.     

Synthesis and Biological Activity of 1,2-Dithiolanes and 1,2-Dithianes Bearing a Nitrogen-containing Substituent

A series of 1,2-dithiolanes, 1,2-dithianes and related compounds bearing a nitrogen-containing substituent were synthesized and their pesticidal activity was tested. A new general synthetic route to 1,2-dithiolanes was established from 1,3-diols. A variation in the position and character of the nitrogen atom is shown to be allowable to some extent for promoting insecticidal activity, unlike the case of sulfur atoms. Most compounds showed acaricidal activity, the strongest being displayed by cis-3,5-bis(dimethylaminomethyl)-1,2-dithiolane.     

Structure-activity relationships of a novel series of melanin-concentrating hormone (MCH) receptor antagonists

A new series of 2-aminoquinolines has been identified as antagonists of the melanin concentrating hormone receptor (MCH-1R). Syntheses and structure-activity relationships are described leading to a compound having low nanomolar activity against the receptor and demonstrating functional antagonism. Studies also showed that some of the compounds were selective against a range of other G protein-coupled receptors.     

Design, synthesis, and vasorelaxant and platelet antiaggregatory activities of coumarin-resveratrol hybrids

We have synthesized the coumarin-resveratrol hybrid 4 and its dimethoxy derivative 3 by a very direct synthetic route involving a Pechmann procedure. Compound 4 has also been synthesized by an alternative route (Perkin), which also allowed the synthesis of compounds 9-13. In addition, we have evaluated the potential vasorelaxant activity of the new compounds in endothelium-containing rat aorta rings pre-contracted with noradrenaline, as well as the inhibitory effects on platelet aggregation induced by thrombin in washed human platelets. The compounds reported here relaxed vascular smooth muscle and inhibited platelet aggregation with a profile similar to that of trans-resveratrol (t-RESV) and, in some cases, showed activity higher than that of the natural compound. This is the case for compound 13, which has a vasorelaxant activity that is twice as high as that of t-resveratrol and a platelet antiaggregant activity that is six times higher. These results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of new vasodilatory and platelet antiaggregatory drugs.     

A new generation of adenosine receptor antagonists: from di- to trisubstituted aminopyrimidines

New adenosine receptor ligands were designed as hybrid structures between previously synthesized substituted dicyanopyridines and aminopyrimidines, yielding two series of cyano-substituted diphenylaminopyrimidines. We were interested in assessing the effect of this substitution pattern on both affinity and intrinsic activity, as the dicyanopyridines comprised both agonists and inverse agonists, whereas the original aminopyrimidines were exclusively inverse agonists. It was found that the new compounds were generally selective for adenosine A(1) receptors, although affinity for the adenosine A(2A) receptor was also noticed for some of the compounds. In a cAMP second messenger assay the compounds behaved as inverse agonists rather than agonists. Among the more A(1) receptor-selective compounds were 5 (LUF6048), 27 (LUF6040) and 53 (LUF6056) with K(i) values of 8.1, 1.2 and 5.7nM, respectively.     

Synthesis and CNS Activity of Some Fluorine Containing 3-Indolylglyoxamides and Tryptamines

A number of new 5-/6-fluoro-2-substitutedaryl-3-indolylglyoxamides and their corresponding tryptamines have been synthesized. 5-/6-Fluoro-2-arylindoles, prepared by Fischer indole synthesis on treatment with oxalyl chloride and subsequent reaction with secondary amines, gave 5-/6-fluoro-2-aryl-3-indolylglyoxamides. The indolylglyoxamides were reduced with lithium aluminium hydride to yield corresponding tryptamines. All the synthesized compounds have been characterized by IR, PMR and ¹⁹F NMR spectral studies. CNS activity of some representative compounds has also been evaluated.     

Preparation and biological activity of 6-benzylaminopurine derivatives in plants and human cancer cells

To study the structure-activity relationships of aromatic cytokinins, the cytokinin activity at both the receptor and cellular levels, as well as CDK inhibitory and anticancer properties of 38 6-benzylaminopurine (BAP) derivatives were compared in various in vitro assays. The compounds were prepared by the condensation of 6-chloropurine with corresponding substituted benzylamines. The majority of synthesised derivatives exhibited high activity in all three of the cytokinin bioassays employed (tobacco callus, wheat senescence and Amaranthus bioassay). The highest activities were obtained in the senescence bioassay. For some compounds tested, significant differences of activity were found in the bioassays used, indicating that diverse recognition systems may operate and suggesting that it may be possible to modulate particular cytokinin-dependent processes with specific compounds. Position-specific steric and hydrophobic effects of different phenyl ring substituents on the variation of biological activity were confirmed. In contrast to their high activity in bioassays, the BAP derivatives were recognised with much lower sensitivity than trans-zeatin in both Arabidopsis thaliana AHK3 and AHK4 receptor assays. The compounds were also investigated for their effects on cyclin-dependent kinase 2 (CDK2) and for antiproliferative properties on cancer and normal cell lines. Several of the tested compounds showed stronger inhibitory activity and cytotoxicity than BAP. There was also a significant positive correlation of the inhibitory effects on human and plant CDKs with cell proliferation of cancer and cytokinin-dependent tobacco cells, respectively. This suggests that at least a part of the antiproliferative effect of the new cytokinins was due to the inhibition of CDK activity.     

Synthesis and pharmacological evaluation of a novel series of 3-aryl-2-(2-substituted-4-methylthiazole-5-yl)thiazolidin-4-one as possible anti-inflammatory and antimicrobial agents

A new series of 3-aryl-2-(2-aryl/benzyl-4-methylthiazole-5-yl)thiazolidin-4-one was synthesized by condensation of 2-aryl/benzyl-4-methylthiazole-5-carbaldehyde, aromatic amines and thioglycolic acid in toluene. All the synthesized compounds are characterized by IR, NMR and elemental or mass analysis. Sixteen out of the newly synthesized compounds were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema method. Some of the synthesized compounds exhibited good anti-inflammatory activity compared with indomethacin. The synthesized compounds were also evaluated for their in vitro antimicrobial activity. Some of the compounds showed mild antibacterial activity while most of the compounds showed good antifungal activity.     

Synthesis and biological activities of 2-oxocycloalkylsulfonamides

A series of novel 2-oxocycloalkylsulfonamides (4) were synthesized and their structures confirmed by IR, (1)H NMR, and elemental analysis. The bioassay showed that they have fair to excellent fungicidal activities against Botrytis cinerea Pers and Sclerotinia sclerotiorum. Among them, compounds 4A(10), 4A(11), 4A(12), 4B(2), and 4B(3), the EC(50) values of which were 2.12, 3.66, 3.96, 2.38, and 2.43 microg/mL, respectively, displayed excellent fungicidal activity against B. cinerea Pers, and are comparable with commercial fungicide procymidone (the EC(50) value is 2.45 microg/mL). 3D QSAR against B. cinerea Pers was studied, a statistically significant and chemically meaningful CoMFA model was developed and some compounds which have a high predicted activity were forecasted. In addition, the bioassay also showed that the compounds have good inhibitory activities against human tumor cells HL-60, BGC-823, Bel-7402 and KB. It is interesting to point out that the antitumor activities of compounds 4 are in accordance with their fungicidal activity to a great extent: compounds having relatively best antitumor activities (4A(10), 4A(11), 4A(12), and 4B(3)) also displayed excellent fungicidal activity.     

Design, synthesis, and biological evaluation of alcyopterosin A and illudalane derivatives as anticancer agents

The synthesis of alcyopterosin A and a series of new derivatives possessing an illudalane skeleton is described. The DNA binding properties of these compounds have been examined and compared to those of reference drugs using a UV spectroscopy technique. The antitumor activity of selected compounds against a panel of 60 human tumor cell lines was tested in the in vitro anticancer screening of the National Cancer Institute. Redox properties were also evaluated. Tested compounds showed significant DNA affinity, derivatives 6 and 15 exhibited remarkable antiproliferative activity and have been identified as new leads in the antitumor strategies.     

基于微管蛋白和秋水仙碱结合位点化合物构建3D-药效团新模型及先导物虚拟筛选

基于作用于微管蛋白秋水仙碱结合位点的小分子抑制剂与生物靶标的复合晶体结构,采用分子模拟软件Discovery Studio 3.0的受体-配体药效团产生程序建立了系列3D药效团新模型（M1-M6）,并用20个已知微管抑制剂验证了其可靠性.用新药效团模型对约10000个化合物的数据库进行了虚拟筛选,发现了一些潜在先导物.据此合成的二芳烃胺类新化合物20在抑制人白血细胞K562的初步实验中显示出了明显的细胞形态变化和抑制活性,对多种人癌细胞A549,KB,KBvin和DU145均有较强的抑制活性（GI500.17～1.02μmol/L）,表明以此新构建的药效团模型进行理性设计和寻找新型抗癌先导物的方法具有一定的可行性.