RESUMEN
The effects of 3 bufadienolides, namely kalantuboside B, kalantuboside A, and bryotoxin C, isolated from Kalanchoe tubiflora (Harvey) were evaluated and characterized in CL1-5 highly metastatic human lung cancer cells. In contrast to their apoptosis-promoting activity in other cancer cells, these bufadienolides only slight or did not induce apoptosis in CL1-5 cancer cells. Instead, they activated an autophagy pathway, as indicated by increased autophagosome formation. Autophagy induced by these bufadienolides was demonstrated to be linked to the down-regulation of p-mTOR and the up-regulation of LC3-II, ATG5, ATG7, and Beclin-1. Our findings revealed an autophagy as the alternative mechanism of drug action by bufadienolides in CL1-5 lung cancer cells and provided evidence that bufadienolides are a potential therapeutic strategy for highly metastatic human lung cancer.
Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Bufanólidos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Bufanólidos/síntesis química , Bufanólidos/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
Bufadienolides are a type of natural cardiac steroids and originally isolated from the Traditional Chinese Medicine Chan'Su, they have been used for the treatment of heart disease in traditional remedies as well as in modern medicinal therapy with potent anti-tumor activities. Due to their unique molecular structures with unsaturated six-membered lactones attached to the steroid core, bufadienolides have received great attention in the synthetic organic community. This review presents total synthetic efforts to some representative bufadienolides, chemical modification of bufadienolides will also be given to discuss their structure-activity relationship in anti-tumor.
Asunto(s)
Bufanólidos/síntesis química , Animales , Línea Celular Tumoral , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Arenobufagin is a naturally occurring bufadienolide showing promising antitumor activity accompanied however with apparent cardiac toxicity. Following the recent discovery that oxidative damage possibly be an important cause of the cardiac toxicity of cardenolides, a strategy fusing the antitumor agent arenobufagin with a benzoisoselenazol fragment, a reactive oxygen species (ROS) scavenger, has been developed. Six novel hybrids were synthesized and their ROS scavenging activities as well as their in vitro cytotoxicity against the human hepatocellular carcinoma cell line HepG2, an adriamycin-resistant subline HepG2/ADM, and the human myocardial cell line AC16 were evaluated. The results indicate that the hybrids exhibit various degrees of in vitro ROS scavenging activities, and weaker cytotoxicity than that of arenobufagin against the myocardial cell line AC16. These findings suggest the feasibility of a strategy in which the cardiotoxicity of the potential antitumor agent arenobufagin is reduced.
Asunto(s)
Antineoplásicos/farmacología , Bufanólidos/farmacología , Cardiotoxicidad/prevención & control , Depuradores de Radicales Libres/farmacología , Compuestos de Organoselenio/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Bufanólidos/síntesis química , Bufanólidos/química , Bufanólidos/toxicidad , Línea Celular Tumoral , Diseño de Fármacos , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/toxicidad , Humanos , Estructura Molecular , Miocitos Cardíacos/patología , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/toxicidad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Covering: early studies through to March 2016Cardenolides and bufadienolides constitute an attractive class of biologically active steroid derivatives which have been used for the treatment of heart disease in traditional remedies as well as in modern medicinal therapy. Due to their application as therapeutic agents and their unique molecular structures, bearing unsaturated 5- or 6-membered lactones (or other heterocycles) attached to the steroid core, cardio-active steroids have received great attention, which has intensified during the last decade, in the synthetic organic community. Advances in the field of cross-coupling reactions have provided a powerful tool for the attachment of lactone subunits to the steroid core. This current review covers a methodological analysis of synthetic efforts to cardenolide and bufadienolide aglycones. Special emphasis is given to cross-coupling reactions applied for the attachment of lactone subunits at sterically very hindered positions of the steroid core. The carefully selected partial and total syntheses of representative cardio-active steroids will also be presented to exemplify recent achievements (improvements) in the field.
Asunto(s)
Bufanólidos/síntesis química , Cardenólidos/síntesis química , Esteroides/síntesis química , Bufanólidos/química , Cardenólidos/química , Estructura Molecular , Esteroides/químicaRESUMEN
Cardiotonic steroids (CTS) are clinically important drugs for the treatment of heart failure owing to their potent inhibition of cardiac Na(+), K(+)-ATPase (NKA). Bufadienolides constitute one of the two major classes of CTS, but little is known about how they interact with NKA. We report a remarkable stereoselectivity of NKA inhibition by native 3ß-hydroxy bufalin over the 3α-isomer, yet replacing the 3ß-hydroxy group with larger polar groups in the same configuration enhances inhibitory potency. Binding of the two (13)C-labelled glycosyl diastereomers to NKA were studied by solid-state NMR (SSNMR), which revealed interactions of the glucose group of the 3ß- derivative with the inhibitory site, but much weaker interactions of the 3α- derivative with the enzyme. Molecular docking simulations suggest that the polar 3ß-groups are closer to the hydrophilic amino acid residues in the entrance of the ligand-binding pocket than those with α-configuration. These first insights into the stereoselective inhibition of NKA by bufadienolides highlight the important role of the hydrophilic moieties at C3 for binding, and may explain why only 3ß-hydroxylated bufadienolides are present as a toxic chemical defence in toad venom.
Asunto(s)
Bufanólidos/química , Bufanólidos/farmacología , Glicósidos Cardíacos/farmacología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Animales , Bufanólidos/síntesis química , Bufonidae , Isótopos de Carbono , Espectroscopía de Resonancia Magnética con Carbono-13 , Glicósidos Cardíacos/química , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Simulación del Acoplamiento Molecular , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Estereoisomerismo , TemperaturaRESUMEN
A series of bufalin-3-yl nitrogen-containing-carbamate derivatives 3 were designed, synthesized, and evaluated for their proliferation inhibition activities against human cervical epithelial adenocarcinoma (HeLa) cell line. The structure-activity relationships (SARs) of this new series are described in this paper. Cytotoxicity data revealed that the C3 moiety had an important influence on cytotoxic activity. Compound 3i-HCl exhibited significant in vitro antiproliferative activity against the ten tested tumor cell lines, with IC50 values ranging from 0.30 to 1.09 nM. Furthermore, 3i-HCl can significantly inhibit tumor growth by 100% at the dose 2 mg/kg by iv, or 4 mg/kg by ig.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bufanólidos/síntesis química , Bufanólidos/farmacología , Carbamatos/química , Nitrógeno/química , Antineoplásicos/química , Bufanólidos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Técnicas de Química Sintética , HumanosRESUMEN
A synthesis of putative bufopyramide has shown the structure assigned to the natural product to be incorrect. The spectroscopic data for the natural product bufopyramide matches that obtained from a synthetic sample of bufoserotonin C, confirming that the two natural products are not distinct, but instead the same compound.
Asunto(s)
Alcaloides/química , Alcaloides/síntesis química , Bufanólidos/química , Bufanólidos/síntesis química , Imidas/química , Imidas/síntesis química , Medicina Tradicional China , Serotonina/análogos & derivados , Espectroscopía de Resonancia Magnética , Serotonina/síntesis química , Serotonina/químicaRESUMEN
A new synthetic analog of bufadienolide, methyl isobryophyllinate A (1), and a known synthetic analog, methyl isobersaldegenate-1,3,5-orthoacetate (2), were obtained by methanolysis of bryophyllin A (3) and bersaldegenin-1,3,5-orthoacetate (5) in basic solution. Structure-insecticidal activity relationship studies revealed both orthoacetate and alpha-pyrone moieties seemed to be essential structural elements for exhibiting insecticidal activity, whereas oxygenated substituents in the C ring enhanced the insecticidal activity against the third instar larvae of silkworm (Bombyx mori).
Asunto(s)
Bufanólidos/farmacología , Insecticidas/síntesis química , Insecticidas/farmacología , Animales , Bombyx/efectos de los fármacos , Bufanólidos/síntesis química , Bufanólidos/química , Insecticidas/química , Larva/efectos de los fármacos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Bufalin possesses a strong anti-cancer effect, but the cardiac toxicity targeting the Na(+), K(+)-ATPase limits its application. Here, two bufalin derivatives, bufadienolactam (1) and secobufalinamide (2), were synthesised by treating bufalin with ammonium acetate in dimethylformamide solution. Their structures were elucidated by extensive spectroscopic methods. The structure of compound 2 was further confirmed by single-crystal X-ray diffraction analysis. Compounds 1 and 2 expressed strong inhibitory activities against androgen-dependent prostate cancer cells (IC50 values about 10 µM), but only weak inhibition on Na(+), K(+)-ATPase (Ki about 70 µM), indicating that they might be potential anti-prostate cancer agents without severe cardiac toxicity.
Asunto(s)
Bufanólidos/síntesis química , Bufanólidos/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Antineoplásicos/farmacología , Bufanólidos/química , Humanos , Concentración 50 Inhibidora , Masculino , Resonancia Magnética Nuclear BiomolecularAsunto(s)
Productos Biológicos/síntesis química , Bufanólidos/síntesis química , Cardenólidos/síntesis química , Productos Biológicos/química , Bufanólidos/química , Cardenólidos/química , Celastraceae/química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
A series of bufalin 3-nitrogen-containing-ester derivatives (2-6) were designed, synthesized, and evaluated for their proliferation inhibition activities against human cervical epithelial adenocarcinoma (HeLa) and non-small-cell lung cancer (A549) cell lines. The structure-activity relationships (SARs) of this new series were described in this paper. Cytotoxicity data revealed that C3 moiety had important influence on cytotoxic activity. On two cell lines, the bufalin-3-piperidinyl-4-carboxylate compound 2 (IC50 values on HeLa and A549 cell lines were 0.76 nM and 0.34 nM, respectively) displayed a significant cytotoxic potency compared to the parent compound bufalin.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Bufanólidos/química , Bufanólidos/farmacología , Nitrógeno/química , Antineoplásicos/síntesis química , Bufanólidos/síntesis química , Técnicas de Química Sintética , Ésteres , Células HeLa , Humanos , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
20R,21R-Epoxyresibufogenin-3-formate (1) and 20S,21S-epoxyresibufogenin-3-formate (2) were synthesized from commercial resibufogenin (3) using known procedures. The major product (1) was dextrorotatory, as was the major product from the reported synthesis of epoxyresibufogenin-3-formate; however, the literature (+)-compound was assigned the 20S,21S-configuration on the basis of NMR data. We have now unequivocally determined, using single-crystal X-ray structure analyses of the major and minor products of the synthesis and of their derivatives, that the major product from the synthesis was (+)-20R,21R-epoxyresibufogenin-3-formate (1). Our minor synthetic product was determined to have the (-)-20S,21S-configuration (2). The (+)-20R,21R-compound 1 has been found to have high affinity for the IL-6 receptor and to act as an IL-6 antagonist. A greatly improved synthesis of 1 was achieved through oxidation of preformed resibufogenin-3-formate. This has enabled us to prepare, from the very expensive commercial resibufogenin, considerably larger quantities of 1, the only known nonpeptide small-molecule IL-6 antagonist.
Asunto(s)
Bufanólidos/síntesis química , Bufanólidos/farmacología , Formiatos/síntesis química , Formiatos/farmacología , Receptores de Interleucina-6/antagonistas & inhibidores , Bufanólidos/química , Cristalografía por Rayos X , Formiatos/química , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
Starting from hellebrigenin, orally cardiotonic active acylcardiosteroid derivatives have been synthesized. D 12316 (acrihellin), the hellebrigenin-3 beta-dimethylacrylate, has been chosen for clinical evaluation.
Asunto(s)
Bufanólidos/síntesis química , Glicósidos Cardíacos/síntesis química , Animales , Bufanólidos/metabolismo , Bufanólidos/farmacología , Glicósidos Cardíacos/metabolismo , Glicósidos Cardíacos/farmacología , Gatos , Fenómenos Químicos , Química , Digoxina/farmacología , ElectrocardiografíaRESUMEN
14-Hydroxy-3beta-[4-O-methyl-alpha-L-rhamnopyranosyl)oxy]-14beta-bufa-4,20,22-trienolide (meproscillarin) is a new semisynthetic glycoside for the therapy of cardiac insufficiency. The preparation from proscillaridin and the chemical and physical properties are described.