RESUMO
In this study we report the synthesis and activity against bovine viral diarrhea virus (BVDV) of a novel series of bicycle δ-sultones containing γ-lactones. BVDV is responsible for major losses in cattle. Some of the synthesized δ-sultones showed pronounced anti-BVDV activity with EC50 values of 0.12-1.0µM and no significant cytotoxicity. Among them, the ortho bromosubstituted derivative 4f (EC50=0.12µM) showed better antiviral activity than other derivatives and was 10 fold more that of than positive control ribavirin (EC50=1.3µM). BVDV is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. The above results provided a novel candidate for the development of anti-HCV agents.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Animais , Bovinos , Modelos Animais de Doenças , Desenho de FármacosRESUMO
In the present study, andrographolide (Andro, 1) derivatives were screened to identify potent inhibitors against tumor-cell migration and invasion, and associated structure-activity relationships were studied. Compared to 1, compounds 8a-8d exhibited more potent activities against migration in SGC-7901, PC-3, A549, HT-29 and Ec109 cell lines. Improved activities against tumor-cell migration and invasion were proved to be associated with the down-regulation of MMPs.
Assuntos
Movimento Celular/efeitos dos fármacos , Diterpenos/química , Diterpenos/farmacologia , Neoplasias/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Diterpenos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Neoplasias/patologia , Relação Estrutura-AtividadeRESUMO
Andrographolide (1) is a major diterpene lactone exhibiting anti-inflammatory effects and is found in the plant Andrographis paniculata (Burm. f) Nees, which is widely used in Traditional Chinese Medicine. Synthesis of more effective drugs from andrographolide is very interesting and can prove to be highly useful. In this study, we investigated the anti-inflammatory effects of andrographolide and its derivatives (compounds 2-6) through dimethylbenzene-induced ear edema in mice. Substances under study were administrated intragastrically and the structure-activity relationship was analyzed. Results showed that compounds 5 and 6 significantly inhibited ear edema compared with compound 1 (p<0.05), indicating that the introduction of p-Chlorobenzylidene to C-15 of compound 2 enhances the anti-inflammatory effect. Moreover, compound 6 exhibited the strongest anti-inflammatory effect against ear edema in mice (79.4%; 1.35 mmol/kg, ig) and paw edema in rats (50.4%; 0.90 mmol/kg, ig). In addition, compound 6 significantly (p<0.05) inhibited granuloma formation and reduced the increase in vascular permeability induced by peritoneal injection of 0.6% acetic acid solution in mice. Findings indicate that compound 6 exerts its enhanced anti-inflammatory effects by decreasing serum iNOS activity, NO production, and PGE(2) production.
Assuntos
Anti-Inflamatórios/farmacologia , Dinoprostona/biossíntese , Diterpenos/química , Diterpenos/farmacologia , Otopatias/tratamento farmacológico , Edema/tratamento farmacológico , Óxido Nítrico/biossíntese , Animais , Compostos de Benzilideno , Otopatias/induzido quimicamente , Edema/induzido quimicamente , Granuloma/tratamento farmacológico , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II/sangue , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xilenos/toxicidadeRESUMO
A series of novel 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives were synthesized and characterized by NMR, HRMS. The pregnenolone (1) was first biotransformed by Mucor circinelloides var lusitanicus to 3beta, 7alpha, 11alpha-trihydroxy-pregn-5-en-20-one (3), then 3 was treated with various benzaldehydes to produce 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives. These derivatives showed remarkable activity against EC109 cells. The absolute configuration of 3 was also confirmed by signal-crystal X-ray analysis.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pregnenolona/análogos & derivados , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Mucor/metabolismo , Pregnenolona/síntese química , Pregnenolona/química , Pregnenolona/farmacologia , Relação Estrutura-AtividadeRESUMO
By means of functional interconversions in ring D of the tetracyclic diterpene isosteviol (ent-16-ketobeyeran-19-oic acid 1), various 15- and 16-substituted isosteviol derivatives were stereoselectively prepared. The cytotoxic activities in vitro of these new isosteviol derivatives were investigated, and some of them showed noteworthy activities against B16-F10 melanoma cells.
Assuntos
Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/farmacologia , Animais , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Simulação por Computador , Cristalografia por Raios X/métodos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Melanoma Experimental/tratamento farmacológico , Camundongos , Modelos Químicos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Considerable interest has been attracted in isosteviol and its derivatives because of their large variety of pharmacological activities. In this project, a series of novel compounds containing hydroxyl, hydroxymethyl group and heteroatom-containing frameworks fused with isosteviol structure were synthesized and evaluated as alpha-glucosidase inhibitors, aimed at clarifying the structure-activity correlation. The results indicated that these isosteviol derivatives were capable of inhibiting in vitro alpha-glucosidase with moderate to good activities. Among them, indole derivative 15b exhibited the highest activities and thus may be exploitable as a lead compound for the development of potent alpha-glucosidase inhibitors.
Assuntos
Diterpenos do Tipo Caurano/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Glicosídeo Hidrolases , Cristalografia por Raios X , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Inibidores Enzimáticos/química , Hidroxilação , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Andrographolide (1), the cytotoxic agent of the plant Andrographis paniculata, was subjected to semi-synthetic studies leading to a series of new derivatives, a novel family of glucosidase inhibitors. Nicotination of 3,19-hydroxyls in 15-alkylidene andrographolide derivatives (9) was favorable to alpha-glucosidase inhibition activity. Among them, 15-p-chlorobenzylidene-14-deoxy-11,12-didehydro-3,19-dinicotinateandrographolide (11c) was a very potent inhibitor against alpha-glucosidase with an IC50 value of 6 microM. However, all compounds concerned for beta-glucosidase showed no inhibition. All compounds synthesized were characterized by the analysis of NMR, IR, HRMS spectra and the stereochemistry of 2 was confirmed by X-ray analysis.
Assuntos
Diterpenos/síntese química , Inibidores Enzimáticos/síntese química , Inibidores de Glicosídeo Hidrolases , Andrographis/química , Diterpenos/farmacologia , Inibidores Enzimáticos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
Condensation of a new unnatural sugar 1 with 1,3-dicarbonyl compounds in the presence of anhydrous zinc chloride gave the polyhydroxyalkyl-furans in excellent yields. Further modification afforded the corresponding furanosyl alpha-C-glycoside derivatives. The absolute configuration of 3-acetyl-2-methyl-5-(2'-chloro-D-galacto-tetritol-1-yl)-furan was confirmed by single-crystal X-ray analysis. The in vitro cytotoxic activities of these furanosyl C-glycosides were also investigated.
Assuntos
Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Fucose/análogos & derivados , Furanos/química , Glicosídeos/farmacologia , Neoplasias Pulmonares/patologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Cloretos/química , Fucose/química , Glicosídeos/síntese química , Humanos , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade , Compostos de Zinco/químicaRESUMO
N(3)-Hydroxyethyltegafur (3) was synthesized in 91.0% yield under a new condition. A series of novel fatty acid esters of 3 were synthesized. These fatty acid-nucleoside conjugates have shown cytotoxicities against Ec9706 cells and A549 cells, and the structure activity relationship was discussed.
Assuntos
Antimetabólitos Antineoplásicos/síntese química , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ácidos Graxos/síntese química , Ácidos Graxos/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Tegafur/análogos & derivados , Tegafur/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Tegafur/farmacologiaRESUMO
A novel and efficient method for the synthesis of quinoxaline derivatives has been developed. Isopropylidenation of 4-chloro-4-deoxy-alpha-D-galactose with 2,2-dimethoxypropane, followed by selective hydrolysis, afforded 2,3-O-isopropylidene-4-chloro-4-deoxy-D-galactose di-methyl acetal (3) as a sole product. Oxidation of compound 3 with (Bu3Sn)2O-Br2 gave corresponding hex-5-ulose derivative in high yields. The hex-5-ulose derivative reacted with o-phenylenediamines under neutral conditions to afford quinoxaline derivatives in reasonable yields. The in vitro cytotoxic activities of these quinoxaline derivatives were investigated.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fucose/análogos & derivados , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Carboidratos/química , Linhagem Celular Tumoral , Fucose/síntese química , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Sais de Tetrazólio , TiazóisRESUMO
A series of analogues of andrographolide were synthesized and evaluated as novel alpha-glucosidase inhibitors. Among them compound 23, 15-p-methoxylbenzylidene 14-deoxy-11,12-didehydroandrographolide, was a potent inhibitor against alpha-glucosidase whose IC(50) value was 16microM. The structure-activity relationships were also discussed.
Assuntos
Diterpenos/química , Diterpenos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Glicosídeo Hidrolases , Animais , Ratos , Relação Estrutura-AtividadeRESUMO
Some novel spiro-tetrahydroquinolines were stereoselectively synthesized by using keto-sugar derived from sucrose as a building block in one pot under mild conditions. The in vitro immunobiological activity and cytotoxicity of these novel tetrahydroquinolines were investigated. The results implied that these spiro-compounds have obvious bioactivity and may be structurally modified to improve bioactivity further.