RESUMO
Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant Croton kongensis followed by the structural modification led to the construction of a small ent-kaurane diterpenoid library (1-25). With subsequent biological screening, 20 highly potent compounds (IC50s < 3 µM) were identified. Among them, 8,9-seco-ent-kaurane 6 displayed comparable activity (IC50s â¼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,ß-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo, 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Croton/química , Diterpenos do Tipo Caurano/farmacologia , Descoberta de Drogas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Rebaudioside E, one of the minor components of steviol glycosides, was first isolated and identified from Stevia rebaudiana in 1977. It is a high-intensity sweetener that tastes about 150-200 times sweeter than sucrose and is also a precursor for biosynthesis of rebaudioside D and rebaudioside M, the next-generation Stevia sweeteners. In this work, new unknown steviol glycosides were enzymatically synthesized from stevioside by coupling UDP-glucosyltransferase UGTSL2 from Solanum lycopersicum and sucrose synthase StSUS1 from Solanum tuberosum. Rebaudioside E was speculated to be the main product of glucosylation of the Glc(ß1âC-19) residue of stevioside along with the formation of a (ß1â2) linkage based on the analysis of the regioselectivity and stereoselectivity of UGTSL2, and verified afterwards by LC-MS/MS with standard. In a 20-ml bioconversion reaction of 20 g/l stevioside by UGTSL2 and StSUS1, 15.92 g/l rebaudioside E was produced for 24 h.
Assuntos
Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/síntese química , Glucosídeos/química , Glicosiltransferases/química , Proteínas de Plantas/química , Solanum lycopersicum/enzimologia , Glucosiltransferases/química , Solanum tuberosum/enzimologiaRESUMO
BACKGROUND: Rabdosia japonica has been historically used in China as a popular folk medicine for the treatment of cancer, hepatitis, and gastricism. Glaucocalyxin A (GLA), an ent-kaurene diterpene isolated from Rabdosia japonica, is one of the main active ingredients showing potent inhibitory effects against several types of tumor cells. To the best of our knowledge, studies regarding the structural modification and Structure- Activity Relations (SAR) of this compound have not yet been reported. OBJECTIVE: The aim of this study was to discover more potent derivatives of GLA and investigate their SAR and cytotoxicity mechanisms. METHODS: Novel 7-O- and 14-O-derivatives of GLA were synthesized by condensation of acids or acyl chloride. The anti-tumor activities of these derivatives against various human cancer cell lines were evaluated in vitro by MTT assays. Apoptosis assays of compound 17 (7,14-diacylation product) were performed on A549 and HL-60 cells by flow cytometry and TUNNEL. The acute toxicity of this compound was tested on mice, at the dose of 300mg per kg body weight. RESULTS: Seventeen novel 7-O- and 14-O-derivatives of GLA (1-17) were synthesized. These compounds showed potent cytotoxicity against the tested cancer cell lines, and almost all of them were found to be more cytotoxic than GLA and oridonin. Of the synthesized derivatives, compound 17 presented the greatest cytotoxicity, with IC50 values of 0.26µM and 1.10µM in HL-60 and CCRF-CEM cells, respectively. Furthermore, this compound induced weak apoptosis of A549 cells but showed great potential in stimulating the apoptosis of HL- 60 cells. Acute toxicity assays indicated that compound 17 is relatively safer. CONCLUSION: The results reported herein indicate that the synthesized GLA derivatives exhibited greater cytotoxicity against leukemia cells than against other types of tumors. In particular, 7,14-diacylation product of GLA was found to be an effective anti-tumor agent. However, the cytotoxicity mechanism of this product in A549 cells is expected to be different than that in other tumor cell lines. Further research is needed to confirm this hypothesis.
Assuntos
Antineoplásicos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Oridonin is one of the major components isolated from Isodon rubescens, a traditional Chinese medicine, and it has been confirmed to exhibit many kinds of biological activities including anticancer, anti-inflammation, antibacterial and so on. However, the poor pharmaceutical property limits the clinical applications of oridonin. So many strategies have been explored in the purpose of improving the potencies of oridonin, and structure modification is one thus way. This review outlines the landscape of the recent development of oridonin derivatives with diverse pharmacological activities, mainly focusing on the biological properties, structure-activity relationships, and mechanism of actions.
Assuntos
Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Descoberta de Drogas/métodos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Diterpenos do Tipo Caurano/síntese química , Humanos , Inflamação/tratamento farmacológico , Isodon/química , Neoplasias/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.
Assuntos
ATPases Transportadoras de Cálcio/metabolismo , Diterpenos do Tipo Caurano/uso terapêutico , Desenho de Fármacos , Plasmodium falciparum/enzimologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Wedelia/química , Antimaláricos/metabolismo , Artemisininas/metabolismo , Cálcio/metabolismo , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/farmacologia , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Tapsigargina/farmacologia , Wedelia/classificaçãoRESUMO
One of the keys for successfully developing drugs against the broad spectrum of cancer cell types is structural diversity. In the current study, we focused on a family of isosteviol derivatives as potential novel antitumor agents. Isosteviol is a tetracyclic diterpenoid obtained by acid hydrolysis of steviol glycoside extracts isolated from abundant Stevia rebaudiana plants. In this work, we have designed and synthesized a panel of isosteviol triazole conjugates using "click" chemistry methodology. Evaluation of these compounds against a series of cancer cell lines derived from primary and metastatic tumors demonstrated that these conjugates exhibit cytotoxic activities with IC50 in the low µM range. In addition, their anti-proliferative activities are cancer cell type specific. Taken together, our studies underscore the importance of structural diversity in achieving cancer cell type specific drug development.
Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Citotoxinas , Diterpenos do Tipo Caurano , Neoplasias/tratamento farmacológico , Triazóis , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Click , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologiaRESUMO
A series of enmein-type derivatives were synthesized and assayed for their antimycobacterial effects. The structures of the synthesized compounds were established by (1)H NMR, (13)C NMR and mass spectral analysis. All the compounds were screened for their antimycobacterial properties against Mycobacterium phlei, Mycobacterium smegmatis and Mycobacterium marinum. Compounds 2, 6g and 6i were found to exhibit potent antimycobacterial activity against M. phlei at a concentration of 0.5 µg/mL, which was comparable to that of positive drug streptomycin. Furthermore, five compounds were tested against Mycobacterium tuberculosis H37Rv based on the promising preliminary screening results. Among them, compound 10 showed potent activity with IC50 value of 17.1 µg/mL against M. tuberculosis H37Rv strain. Thus, compound 10 could emerge as a promising lead for further research work.
Assuntos
Antituberculosos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Diterpenos/farmacologia , Mycobacterium/efeitos dos fármacos , Antituberculosos/síntese química , Diterpenos/síntese química , Diterpenos do Tipo Caurano/síntese química , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
An effective two step transformation of oridonin to 15,16-seco-ent-kaurane skeleton is reported. We also achieved the conversion of one intermediate to natural product rubescensin S and revised its structure as a 13S configuration although 13R is reported in the literature.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Química Farmacêutica/métodos , Diterpenos do Tipo Caurano/síntese química , Medicamentos de Ervas Chinesas/síntese química , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos do Tipo Caurano/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Concentração Inibidora 50 , Isodon/química , Células K562 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , EstereoisomerismoRESUMO
Atractyligenin (1) and several synthetic derivatives were tested and found to be active against tumor cell replication. Compound 1 was readily converted to the 2,15-diketo (3) or 15-keto (4) derivatives, which contain an alpha,beta-unsaturated ketone. Compounds 3 and 4 showed significant cytotoxic activity against all six tested cancer cell lines and were most potent against 1A9 ovarian cancer cells with EC50 values of 0.2 and 0.3 microM, respectively. These two 1-analogues are promising lead compounds for further investigation.