RESUMO
Ulcerative colitis is a chronic inflammatory disease with a remitting-relapsing clinical course, it has evolved into a global burden given its high incidence worldwide. Cantharidin (CTD) derivatives are a class of compounds whose structures characterized with a 7-oxabicyclo [2.2.1]heptane core. Though potent cytotoxicity CTD and its derivatives showed, their clinical usage as anti-cancer drugs was limited by the toxicity in organs. In order to find new CTD analogues with good activity and lower toxicity, 21 CTD analogues with or without alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core were synthesized, some compounds showed better in vitro anti-inflammatory activity compared to CTD and norcantharidin (NCTD). Based on the structure-activity relationship results of in vitro experiment, analogue 3i was chosen for further study. Results from the acute toxicity in mice showed that 3i was hypotoxic with the single-dose MTD (maximum tolerated dose) for oral administration is over 1852 mg/kg, at least 35-fold lower than that of NCTD. Mechanism study indicated that 3i could potently inhibit TNF-α induced activation of NF-κB signaling by down-regulation the expression levels of phosphor- IKK, IκBα, and NF-κB p65, and alleviated dextran sulfate sodium-induced colitis in mice. This study indicated that CTD analogues with alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core is a kind of new compounds with good anti-inflammatory activity and lower toxicity in vivo, and might be used as therapeutic agents for inflammatory diseases.
Assuntos
Colite , NF-kappa B , Animais , Camundongos , Cantaridina/farmacologia , Cantaridina/uso terapêutico , Sulfato de Dextrana , Colite/induzido quimicamente , Colite/tratamento farmacológico , HeptanosRESUMO
We evaluated the protective effect and toxicity of extracts from Mylabris phalerata Pallas by measuring the activated partial thromboplastin time, prothrombin time, venous thrombosis and acute toxicity in rats. Results showed the petroleum ether and water fractions of M. phalerata inhibited thrombosis but hardly prolonged the activated partial thromboplastin time and prothrombin time in rats. The trichloromethane fraction had obvious toxicity with an LD50 of 0.2 g/kg in vivo, and contained many cantharidin analogs (CAs) by ultra-performance liquid chromatography-quadrupole ion trap-tandem mass spectrometry (UPLC-QTRAP-MS/MS). CAs are the major potential bioactivity constituent in M. phalerata. An effective and reliable UPLC-QTRAP-MS/MS method was successfully developed to separate and identify CAs. The fragmentation patterns of five purified compounds were applied to elucidate the structure of their analogs. Thirty-four CAs were characterized or tentatively identified, eight of which are proposed to be novel compounds (13-17, 20, 21, 23), and their fragmentation patterns were investigated for the first time. Most importantly, a rapid and reliable UPLC-MS method was developed to identify the CAs of M. phalerata. This method has contributed to the discovery of most of these unknown analogs or their metabolites in M. phalerata effectively and quickly, and does not rely on limited chemical structural diversity libraries.
Assuntos
Cantaridina , Cromatografia Líquida de Alta Pressão/métodos , Besouros/química , Espectrometria de Massas em Tandem/métodos , Animais , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea , Cantaridina/análogos & derivados , Cantaridina/análise , Cantaridina/química , Cantaridina/farmacologia , Feminino , Fibrinolíticos/análise , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Masculino , RatosRESUMO
Eleven new monoterpenoids including three 1-methyl cantharimide-type derivatives (1-3), five 1,2-dimethyl cantharimide-type derivatives (4, 5, 7-9), and three 1-hydroxymethyl-2-methyl cantharimide-type derivatives (10-12), together with seven known cantharimides (6, 13-18), were isolated from Mylabis phalerata Palla. The planar structures and absolute configurations of compounds 1-14 were fully elucidated on the basis of spectroscopic analysis, ECD spectra, single-crystal X-ray diffraction analysis, and chemical methods. Compounds 6, 15, 16, and 18 were found to be potent inhibitors of HBV virus, with IC50 values of 62, 42, 58, and 19 µM.
Assuntos
Besouros/química , Monoterpenos/isolamento & purificação , Animais , China , Cristalografia por Raios X , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Monoterpenos/química , Monoterpenos/farmacologia , Ressonância Magnética Nuclear BiomolecularRESUMO
Ten compounds were isolated from Mylabris phalerata by using preparative HPLC and column chromatography over MCI gel. On the basis of physical-chemical properties, NMR and MS data analysis, the compounds were identified as 5'-[(1 R,2 R,3 S,6R)-1-hydroxymethyl-2-methyl-3,6-epoxycyclohexane-1,2-dicarboximide]- ethyl-2'-methyl-2'-butenoate (1),cantharidin (2), cyclo-(L-Pro-L-Ala) (3), cyclo-(R-Pro-R-Leu) (4), cyclo-(S-Pro-R-Leu) (5), cyclo-(D-Pro-L-Tyr) (6), indole-3-aldehyde (7), 3-indoleacetic acid (8), valerolactam (9), and 4-hydroxyphthalid (10).Compound 1 was a new compound, and compounds 2-10 were obtained from this genus for the first time. Compounds 1-9 were subjected to cytotoxic activity on HCT-116, HepG2, BGC-823, NCI-H1650, A2780 cell lines, and only compound 2 showed inhibitory effect on all cancer cell lines.