RESUMO
Demethylzeylasteral (DEM), a class of terpenoids isolated from natural plants, frequently exhibits moderate or limited inhibitory effect on tumor growth across multiple cancer types. Thus, here we attempted to elevate the anti-tumor efficacy of DEM by altering active groups in its chemical structure. Initially, we synthesized a series of novel DEM derivatives 1-21 through performing a series of modifications of its phenolic hydroxyl groups at C-2/3, C-4 and C-29 positions. The anti-proliferative activities of these new compounds were subsequently assessed using three human cancer cell line models (A549, HCT116 and HeLa) and CCK-8 assay. Our data showed that compared to original DEM compound, derivative 7 exhibited remarkable inhibition effect on A549 (16.73 ± 1.07 µM), HCT116 (16.26 ± 1.94 µM) and HeLa (17.07 ± 1.09 µM), almost reaching to the same level of DOX. Moreover, the structure-activity relationships (SARs) of the synthesized DEM derivatives were discussed in detail. We found that treatment with derivative 7 only led to moderate cell cycle arrest at S-phase in a concentration-dependent manner. Meanwhile, derivative 7 treatment markedly induced apoptosis in tumor cells. Consistent with this observation, our subsequent docking analysis showed that derivative 7 is capable of activating caspase-3 through interaction with the His 121 and Gly 122 residues of the enzyme. Overall, we have developed a new series of DEM derivatives with elevated anti-tumor efficacy relative to its parent form. The results suggested that derivative 7 has great potential to be employed as an anticancer agent candidate for natural product-based cancer chemotherapy.
Assuntos
Antineoplásicos , Humanos , Estrutura Molecular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Relação Estrutura-Atividade , Apoptose , Proliferação de Células , Simulação de Acoplamento Molecular , Relação Dose-Resposta a DrogaRESUMO
Pentacyclic triterpenoids are important natural products widely presenting in nature with rich bioactivities. Tripterygium wilfordii Hook. f., a precious Chinese medicinal material, is used to cure rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus. Triterpenoids are one of the important active components of Tripterygium wilfordii Hook. f. Demethylzeylasteral extracted from Tripterygium wilfordii Hook. f. had numerous pharmacological effects, including anticancer, anti-inflammatory, immune suppression, anti-fertility, antivirus, antimicrobial. In this paper, we summarized comprehensively pharmacological activities of demethylzeylasteral for potential application as a therapeutic agent.
Assuntos
Medicamentos de Ervas Chinesas , Triterpenos , Tripterygium , Estrutura Molecular , Triterpenos/farmacologia , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
A marine fibrinolytic compound was studied for use in thrombolytic therapy. Firstly, the absorption and transportation characteristics of 2,5-BHPA (2,5-BHPA:2,5-Bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-keto-1,2,7,8-tertahydro-6H-pyran[a]isoindol-2-yl]-pentanoic acid, a novel pyran-isoindolone derivative with bioactivity isolated from a rare marine microorganism in our laboratory) in the human Caco-2 cells monolayer model were investigated. We collected 2,5-BHPA in the cells to calculate the total recovery, and its concentration was analyzed by LC/MS/MS (Liquid Chromatography/ Mass Spectrum/ Mass Spectrum). The results showed that 2,5-BHPA has low permeability and low total recoveries in the Caco-2 cells membrane. Pharmacokinetics and tissue distribution of 2,5-BHPA were investigated in beagle dogs using HPLC (High Performance Liquid Chromatography) after intravenous administration of three different doses (7.5, 5.0, 2.5 mg·kg-1). Pharmacokinetic data indicated that 2,5-BHPA fitted well to a two-compartment model. Elimination half-lives (T1/2) were 49 ± 2, 48 ± 2, and 49 ± 2 min, respectively; the peak concentrations (Cmax) were 56.48 ± 6.23, 48.63 ± 5.53, and 13.64 ± 2.76 µg·mL-1, respectively; clearance rates (CL) were 0.0062 ± 0.0004, 0.0071 ± 0.0008, and 0.0092 ±0.0006 L·min-1·kg-1, respectively; mean retention times (MRT) were 28.17 ± 1.16, 26.23 ± 0.35, and 28.66 ± 0.84 min, respectively. The low penetrability of 2,5-BHPA indicated that the intravenous route of administration is more appropriate than the oral route. Meanwhile, 2,5-BHPA showed a good pharmacokinetic profile in beagle dogs. The tissue distribution showed that 2,5-BHPA could quickly distribute into the heart, intestines, liver, stomach, spleen, lungs, testicles, urine, intestine, kidneys, brain, and feces. The concentration of 2,5-BHPA was higher in the liver and bile. Interestingly, 2,5-BHPA was detected in the brain. Taken together, the above results suggested that our work might be beneficial in the development of agents for thrombolytic treatment.
Assuntos
Organismos Aquáticos/química , Fibrinolíticos/farmacocinética , Isoindóis/farmacocinética , Piranos/farmacocinética , Administração Oral , Animais , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Cães , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/administração & dosagem , Fibrinolíticos/química , Humanos , Injeções Intravenosas , Isoindóis/administração & dosagem , Isoindóis/química , Masculino , Modelos Animais , Permeabilidade , Piranos/administração & dosagem , Piranos/química , Espectrometria de Massas em Tandem , Trombose/tratamento farmacológico , Distribuição TecidualRESUMO
Swerilactonesâ H-K (1-4), which are four novel lactones with an unprecedented C29 skeleton, were isolated from Swertia mileensis (Qing-Ye-Dan), an endemic Chinese herb used for treating viral hepatitis. Their structures were determined by extensive spectroscopic and X-ray crystallographic diffraction analyses. Swerilactonesâ H-K exhibit potent anti-hepatitis B virus activity against HBV DNA replication with IC(50) values ranging from 1.53 to 5.34â µM. For the first time, a plausible biogenetic pathway for swerilactonesâ H-K, together with the previously reported swerilactonesâ A-D is proposed. From a biogenetic point of view, swerilactonesâ A-D are ascribed as secoiridoid dimers, and swerilactonesâ H-K as secoiridoid trimers.
Assuntos
Antivirais/química , Antivirais/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Antígenos de Superfície da Hepatite B/química , Antígenos de Superfície da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/química , Vírus da Hepatite B/efeitos dos fármacos , Iridoides/química , Lactonas/química , Lactonas/isolamento & purificação , Swertia/química , Antivirais/isolamento & purificação , Cristalografia por Raios X , Medicamentos de Ervas Chinesas/isolamento & purificação , Humanos , Concentração Inibidora 50 , Iridoides/farmacologia , Lactonas/farmacologia , Estrutura MolecularRESUMO
OBJECTIVE: To study the effects of lobster sauce and polysaccharide extracts on alpha-1,4-glucosidase activity by establishing on enzyme-inhibitor model. METHODS: Glucosidase activity was assayed at PH optima by PNPG substrate. Lobster sauce extracts were prepared by soaking, centrifagation. Polysaccharide were prepared by soaking, centrifagation, separation. RESULTS: Lobster sauce and polysaccharide can inhibit alpha-1,4-glucosidase. CONCLUSION: This finding suggested that their hypoglycemic mechanism was similar to Acarbose. Lobster sauce may contain phenyalanine.