RESUMEN
The complex and diverse molecular architectures along with broad biological activities of ent-kauranoids natural products make them an excellent testing ground for the invention of synthetic methods and strategies. Recent efforts notwithstanding, synthetic access to the highly oxidized enmein-type ent-kauranoids still presents considerable challenges to synthetic chemists. Here, we report the enantioselective total syntheses of C-19 oxygenated enmein-type ent-kauranoids, including (-)-macrocalyxoformins A and B and (-)-ludongnin C, along with discussion and study of synthetic strategies. The enabling feature in our synthesis is a devised Ni-catalyzed decarboxylative cyclization/radical-polar crossover/C-acylation cascade that forges a THF ring concomitantly with the ß-keto ester group. Mechanistic studies reveal that the C-acylation process in this cascade reaction is achieved through a carboxylation followed by an in situ esterification. Biological evaluation of these synthetic natural products reveals the indispensable role of the ketone on the D ring in their anti-tumor efficacy.
Asunto(s)
Productos Biológicos , Estereoisomerismo , Productos Biológicos/síntesis química , Productos Biológicos/química , Humanos , Ciclización , Línea Celular Tumoral , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Catálisis , Acilación , Animales , Ratones , Níquel/química , Estructura MolecularRESUMEN
Targeting NLRP3 inflammasome with inhibitors is a novel strategy for NLRP3-driven diseases. Herein, hit compound 5 possessing an attractive skeleton was identified from our in-house database of oridonin, and then a potential lead compound 32 was obtained by optimization of 5, displaying two-digit nanomolar inhibition on NLRP3. Moreover, compound 32 showed enhanced safety index (SI) relative to oridonin (IC50 = 77.2 vs 780.4 nM, SI = 40.5 vs 8.5) and functioned through blocking ASC oligomerization and interaction of NLRP3-ASC/NEK7, thereby suppressing NLRP3 inflammasome assembly and activation. Furthermore, diverse agonists-induced activations of NLRP3 could be impeded by compound 32 without altering NLRC4 or AIM2 inflammasome. Crucially, compound 32 possessed tolerable pharmaceutical properties and significant anti-inflammatory activity in MSU-induced gouty arthritis model. Therefore, this work enriched the SAR of NLRP3 inflammasome inhibitors and provided a potential candidate for the treatment of NLRP3-associated diseases.
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Antiinflamatorios , Diterpenos de Tipo Kaurano , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Diterpenos de Tipo Kaurano/farmacología , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/uso terapéutico , Diterpenos de Tipo Kaurano/síntesis química , Inflamasomas/metabolismo , Inflamasomas/antagonistas & inhibidores , Animales , Humanos , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Antiinflamatorios/síntesis química , Relación Estructura-Actividad , Masculino , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Ratones Endogámicos C57BL , Quinasas Relacionadas con NIMA/antagonistas & inhibidores , Quinasas Relacionadas con NIMA/metabolismoRESUMEN
Cardiovascular diseases (CVDs) persist as the predominant cause of mortality, urging the exploration of innovative pharmaceuticals. Mitochondrial dysfunction stands as a pivotal contributor to CVDs development. Sirtuin 3 (SIRT3), a prominent mitochondrial deacetylase known for its crucial role in protecting mitochondria against damage and dysfunction, has emerged as a promising therapeutic target for CVDs treatment. Utilizing isosteviol, a natural ent-beyerene diterpenoid, 24 derivatives were synthesized and evaluated in vivo using a zebrafish model, establishing a deduced structure-activity relationship. Among these, derivative 5v exhibited significant efficacy in doxorubicin-induced cardiomyopathy in zebrafish and murine models. Subsequent investigations revealed that 5v selectively elevated SIRT3 expression, leading to the upregulation of SOD2 and OPA1 expression, effectively preventing mitochondrial dysfunction, mitigating oxidative stress, and preserving cardiomyocyte viability. As a novel structural class of SIRT3 activators with robust therapeutic effects, 5v emerges as a promising candidate for further drug development.
Asunto(s)
Cardiotónicos , Diterpenos de Tipo Kaurano , Diseño de Fármacos , Sirtuina 3 , Pez Cebra , Animales , Sirtuina 3/metabolismo , Sirtuina 3/antagonistas & inhibidores , Diterpenos de Tipo Kaurano/farmacología , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/uso terapéutico , Cardiotónicos/farmacología , Cardiotónicos/síntesis química , Cardiotónicos/química , Cardiotónicos/uso terapéutico , Relación Estructura-Actividad , Ratones , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Humanos , Estrés Oxidativo/efectos de los fármacos , Doxorrubicina/farmacologíaRESUMEN
Nineteen isosteviol derivatives were designed and synthesized by C-16, C-19 and D-ring modifications of isosteviol. These compounds were screened for their cytotoxic activities against Hela and A549 cells in vitro. Among them, the inhibitory effect of compounds 3b and 16 on Hela cells was comparable to that of the positive control gefitinib, and the compounds 3b (IC50=7.84 ± 0.84 µM) and 7a (IC50=6.89 ± 0.33 µM) exhibited significant cytotoxicity superior to gefitinib (IC50=11.02 ± 3.27 µM) against A549 cells.
Asunto(s)
Diterpenos de Tipo Kaurano , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Diterpenos de Tipo Kaurano/farmacología , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Estructura Molecular , Células HeLa , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Células A549 , Gefitinib/farmacología , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Quinazolinas/farmacología , Quinazolinas/química , Quinazolinas/síntesis químicaRESUMEN
Ent-kaurane diterpenes are a large group of natural products, with more than 1,000 compounds since their discovery. Due to their excellent biological activities and complex polycyclic structures, these compounds have attracted organic synthesis chemists around the world to be devoted to achieve their total synthesis. At present, the isolated C-20-oxygenated ent-kaurane diterpenes are the most abundant of these natural products, reaching more than 350 in number. However, only total syntheses of 3,20-epoxy, 7,20-epoxy and 19,20-lactone ent-kaurane diterpenes have been reported. In this review, we elaborate the synthesis of these three types of C-20 oxygenated ent-kaurane natural products, discuss these synthetic strategies in detail, and provide good guidance and reference for the synthesis of other C-20 oxygenated compounds.
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Diterpenos de Tipo Kaurano , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/síntesis química , Oxígeno/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Estructura MolecularRESUMEN
Jiyuan Oridonin A (JOA) is a naturally occurring ent-kaurane diterpenoid that exhibits significant potential in the field of anti-tumor drug development. However, its detailed anti-cancer mechanism of action has not been fully understood. In order to investigate its anticancer mode of action, two series of novel fluorescent derivatives of JOA conjugated with naphthalimide dyes were synthesized, and their antitumor activity against five selected cancer cell lines (MGC-803, SW1990, PC-3, TE-1 and HGC-27) was evaluated. Compared with JOA, the anti-tumor activity of the vast majority of compounds were improved. Among them, B12 exhibited promising anti-proliferative activity against HGC-27 cells with IC50 value of 0.39 ± 0.09 µM. Fluorescence imaging studies demonstrated that probe B12 could enter HGC-27 cells in a dose-dependent and time-dependent manner and was mainly accumulated in mitochondria. Preliminary biological mechanism studies indicated that B12 was able to inhibit cell cloning and migration. Further studies suggested that B12-induced apoptosis was related to the mitochondrial pathway. Overall, our results provide new approaches to explore the molecular mechanism of the natural product JOA, which would contribute to its further development as an antitumor agent.
Asunto(s)
Antineoplásicos/síntesis química , Diterpenos de Tipo Kaurano/química , Colorantes Fluorescentes/química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Relación Estructura-ActividadRESUMEN
Covering: 2015 to 2020The ent-kaurane diterpenoids are integral parts of tetracyclic natural products that are widely distributed in terrestrial plants. These compounds have been found to possess interesting bioactivities, ranging from antitumor, antifungal and antibacterial to anti-inflammatory activities. Structurally, the different tetracyclic moieties of ent-kauranes can be seen as the results of intramolecular cyclizations, oxidations, C-C bond cleavages, degradation, or rearrangements, starting from their parent skeleton. During the past decade, great efforts have been made to develop novel strategies for synthesizing these natural products. The purpose of this review is to describe the recent advances in the total synthesis of ent-kaurane diterpenoids covering the period from 2015 to date.
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Diterpenos de Tipo Kaurano/síntesis química , Diterpenos/síntesis química , Técnicas de Química Sintética/métodosRESUMEN
Steviol glycosides are the intensely sweet components of extracts from Stevia rebaudiana. These molecules comprise an invariant steviol aglycone decorated with variable glycans and could widely serve as a low-calorie sweetener. However, the most desirable steviol glycosides Reb D and Reb M, devoid of unpleasant aftertaste, are naturally produced only in trace amounts due to low levels of specific ß (1-2) glucosylation in Stevia. Here, we report the biochemical and structural characterization of OsUGT91C1, a glycosyltransferase from Oryza sativa, which is efficient at catalyzing ß (1-2) glucosylation. The enzyme's ability to bind steviol glycoside substrate in three modes underlies its flexibility to catalyze ß (1-2) glucosylation in two distinct orientations as well as ß (1-6) glucosylation. Guided by the structural insights, we engineer this enzyme to enhance the desirable ß (1-2) glucosylation, eliminate ß (1-6) glucosylation, and obtain a promising catalyst for the industrial production of naturally rare but palatable steviol glycosides.
Asunto(s)
Diterpenos de Tipo Kaurano/síntesis química , Glucósidos/síntesis química , Glicosiltransferasas/química , Oryza/enzimología , Proteínas de Plantas/química , Edulcorantes/síntesis química , Secuencia de Carbohidratos , Dominio Catalítico , Diterpenos de Tipo Kaurano/metabolismo , Expresión Génica , Glucosa/química , Glucosa/metabolismo , Glucósidos/metabolismo , Glicosilación , Glicosiltransferasas/genética , Glicosiltransferasas/metabolismo , Humanos , Cinética , Modelos Moleculares , Oryza/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Ingeniería de Proteínas/métodos , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Stevia/química , Stevia/enzimología , Especificidad por Sustrato , Edulcorantes/metabolismo , Gusto/fisiología , Uridina Difosfato Glucosa/química , Uridina Difosfato Glucosa/metabolismoRESUMEN
A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C-C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates.
Asunto(s)
Alcaloides/síntesis química , Antineoplásicos/síntesis química , Productos Biológicos/química , Diterpenos de Tipo Kaurano/síntesis química , Compuestos Heterocíclicos/síntesis química , Alcaloides/farmacología , Alquilación , Antineoplásicos/farmacología , Azidas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/farmacología , Radicales Libres/química , Compuestos Heterocíclicos/farmacología , Humanos , Concentración 50 Inhibidora , Yodo/química , Lactamas/química , Pirrolidinas/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Croton/química , Diterpenos de Tipo Kaurano/farmacología , Descubrimiento de Drogas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Advanced gastric cancer (GC) is a significant threat to human health. Oridonin (ORI), isolated from the Chinese herb Rabdosia rubescens, has demonstrated great potential in GC therapy. However, the application of ORI in the clinic was greatly hindered by its poor solubility, low bioavailability, and rapid plasma clearance. Herein, a simple and novel redox-sensitive ORI polymeric prodrug formulation was synthesized by covalently attaching ORI to poly(ethylene glycol)-block-poly(l-lysine) via a disulfide linker, which can self-assemble into micelles (P-ss-ORI) in aqueous solutions and produce low critical micelle concentrations (about 10 mg L-1), characterized by small size (about 80 nm), negative surface charge (about -12 mV), and high drug loading efficiency (18.7%). The in vitro drug release study showed that P-ss-ORI can rapidly and completely release ORI in a glutathione (GSH)-rich environment and under low pH conditions. Moreover, in vitro and in vivo investigations confirmed that P-ss-ORI could remarkably extend the blood circulation time of ORI, enrich in tumor tissue, be effectively endocytosed by GC cancer cells, and quickly and completely release the drug under high intracellular GSH concentrations and low pH conditions, all these characteristics ultimately inhibit the growth of GC. This redox and pH dual-responsive P-ss-ORI formulation provides a useful strategy for GC treatment.
Asunto(s)
Antineoplásicos/farmacología , Diterpenos de Tipo Kaurano/farmacología , Diseño de Fármacos , Polímeros/farmacología , Profármacos/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Micelas , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Polímeros/síntesis química , Polímeros/química , Profármacos/síntesis química , Profármacos/química , Ratas , Ratas Sprague-Dawley , Neoplasias Gástricas/patología , Células Tumorales CultivadasRESUMEN
Tetracyclic diterpenoids (C20) mainly refer to the plant terpenoids bearing biogenetically related carbon skeletons derived from copalyl diphosphates (ent-CPP and syn-CPP). This large family contains over 1600 known members that can be categorized into 11 major structural types. Among them, more than three-quarters share a bridged bicyclo[3.2.1]octane subunit, which is also an important branching point in biosynthesis en route to the other types of bicyclic scaffolds, such as bicyclo[2.2.2]-, bicyclo[3.3.0]-, and tricyclo[3.2.1.0]octanes. Combined with the significance of its stereochemical importance in biological activity, the assembly of the bicyclo[3.2.1]octane skeletons is critical to the success of the whole synthesis blueprint toward tetracyclic diterpenoids. Although a number of inspiring methodologies have been disclosed, general approaches by the incorporation of innovative cascade reactions permitting access to diverse structural types of tetracyclic diterpenoids remain limited and in urgent demand.Because of the long-standing interest in the synthesis of bridged diterpenoids, we have recently developed two complementary types of oxidative dearomatization induced (ODI) cascade approaches to the rapid and efficient construction of bicyclo[3.2.1]octane skeletons. In this Account, we summarize our original synthesis design, methodology development, and the application of these two strategies in tetracyclic diterpenoid synthesis during the past few years in our laboratory.First, we detail our preliminary investigation of the ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade reaction, which showed a wide scope of vinylphenol substrates and led to cyclopentane and cyclohexane-fused bicyclo[3.2.1]octanes in good yields with excellent dr values. Next, we describe the utilization of this ODI-[5 + 2] cascade reaction which resulted in the asymmetric total syntheses of four highly oxygenated ent-kauranoids. The strategy concerning accurate stereochemical control in the ODI-[5 + 2] cycloaddition was then successfully transplanted to the total syntheses of three stemaranoids, thus providing a straightforward and diastereoselective route to C9-ethano-bridged tetracyclic diterpenoids. To access more complex diterpenoid rhodomollanol A, we exploited two additional biomimetic rearrangements, namely, the retro-Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade and the photo-Nazarov cyclization/intramolecular cycloetherification cascade. Taken together with the ODI-[5 + 2] cascade, the asymmetric total synthesis of the target molecule was realized, which shed light on the biogenetic pathway of the unprecedented rhodomollane-type carbon framework. Finally, we describe an ODI-Diels-Alder/Beckwith-Dowd cascade approach as a valuable supplement to the ODI-[5 + 2] cascade for the fabrication of cycloheptane-fused bicyclo[3.2.1]octane skeletons. Its versatility was also demonstrated by the total syntheses of two challenging grayanane diterpenoids. In view of the high functional-group compatibility and scalability, we anticipate that the two novel cascade approaches will find further use in the field of complex natural product synthesis.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Diterpenos/síntesis química , Octanos/química , Reacción de Cicloadición , Diterpenos/química , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Diseño de Fármacos , Oxidación-ReducciónRESUMEN
The field of total synthesis has reached a stage in which emphasis has been increasingly focused on synthetic efficiency rather than merely achieving the synthesis of a target molecule. The pursuit of synthetic efficiency, typically represented by step count and overall yield, is a rich source of inspiration and motivation for synthetic chemists to invent innovative strategies and methods. Among them, convergent strategy has been well recognized as an effective approach to improve efficiency. This strategy generally involves coupling of fragments with similar complexity to furnish the target molecule via subsequent cyclization or late-stage functionalization. Thus, methodologies that enable effective connection of fragments are critical to devising a convergent plan. In our laboratory, convergent strategy has served as a long-standing principle for pursuing efficient synthesis during the course of planning and implementing synthetic projects. In this Account, we summarize our endeavors in the convergent synthesis of natural products over the last ten years. We show how we identify reasonable bond disconnections and employ enabling synthetic methodologies to maximize convergency, leading to the efficient syntheses of over two-dozen highly complex molecules from eight disparate families.In detail, we categorize our work into three parts based on the diverse reaction types for fragment assembly. First, we demonstrate the application of a powerful single-electron reducing agent, SmI2, in a late-stage cyclization step, forging the polycyclic skeletons of structurally fascinating Galbulimima alkaloids and Leucosceptrum sesterterpenoids. Next, we showcase how three different types of cycloaddition reactions can simultaneously construct two challenging C-C bonds in a single step, providing concise entries to three distinct families, namely, spiroquinazoline alkaloids, gracilamine, and kaurane diterpenoids. In the third part, we describe convergent assembly of ent-kaurane diterpenoids, gelsedine-type alkaloids, and several drug molecules via employing some bifunctional synthons. To access highly oxidized ent-kaurane diterpenoids, we introduce the hallmark bicyclo[3.2.1]octane ring system at an early stage, and then execute coupling and cyclization by means of a Hoppe's homoaldol reaction and a Mukaiyama-Michael-type addition, respectively. Furthermore, we showcase how the orchestrated combination of an asymmetric Michael addition, a tandem oxidation-aldol reaction and a pinacol rearrangement can dramatically improve the efficiency in synthesizing gelsedine-type alkaloids, with nary a protecting group. Finally, to address the supply issue of several drugs, including anti-influenza drug zanamivir and antitumor agent Et-743, we exploit scalable and practical approaches to provide advantages over current routes in terms of cost, ease of execution, and efficiency.
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Productos Biológicos/síntesis química , Alcaloides/síntesis química , Alcaloides/química , Productos Biológicos/química , Compuestos Bicíclicos con Puentes/química , Carbono/química , Ciclización , Reacción de Cicloadición , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Octanos/química , Oxidación-Reducción , Sesterterpenos/síntesis química , Sesterterpenos/química , Estereoisomerismo , Trabectedina/síntesis química , Trabectedina/química , Zanamivir/síntesis química , Zanamivir/químicaRESUMEN
A series of conjugates of diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) and N-acetyl-D-glucosamine was synthesised and their cytotoxicity against several human cancer cell lines (M-Hela, MCF-7, Hep G2, Panc-1, PC-3), as well as normal human cell lines (WI-38, Chang liver) was assayed. Most of the conjugates were found to be cytotoxic against the mentioned cancer cell lines in the range of IC50 values 13-89 µM. Two lead compounds 14a and 14b showed selective cytotoxicity against M-Hela (IC50 13 and 14 µM) that was two times as high as the cytotoxicity of the anti-cancer drug Tamoxifen in control (IC50 28 µM). It was found that cytotoxic activity of the lead compounds against M-Hela cells is due to induction of apoptosis.
Asunto(s)
Acetilglucosamina/síntesis química , Acetilglucosamina/farmacología , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/farmacología , Diterpenos/síntesis química , Diterpenos/farmacología , Acetilglucosamina/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Diterpenos/química , Diterpenos de Tipo Kaurano/química , Ensayos de Selección de Medicamentos Antitumorales , Hemólisis/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
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.
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Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/síntesis química , Glucósidos/química , Glicosiltransferasas/química , Proteínas de Plantas/química , Solanum lycopersicum/enzimología , Glucosiltransferasas/química , Solanum tuberosum/enzimologíaRESUMEN
Isosteviol, a prodrug used to be obtained via Wagner-Meerwein rearrangement from steviol with low yield and long reaction time. Herein, an in-situ separation-coupling-reaction is presented to prepare isosteviol from the natural sweetener stevioside. Simply with in-situ water-washing, the product containing 92.98% purity of isosteviol was obtained with a stevioside conversion of 97.23% from a packet bed reactor without further separation. Within the assayed inorganic acid, organic acids and acidic ionic liquids, the acidic ion-exchange resins provided higher product specificity towards isosteviol. Furthermore, comparing to 5-Fluorouracil, the product presented similar and even stronger inhibition on proliferation of the assayed human cancer cells in a time and dose-dependence by causing cell phase arrest. Isosteviol treatment caused G1 arrest on SGC-7901, HCT-8 and HCT-116 cells, S arrest on HepG2, Huh-7 and HepG3B cells, and G2 arrest on MGC-803 cells, respectively. Reaction coupling separation for isosteviol production catalyzed by acidic ion-exchange resin.
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Antineoplásicos , Diterpenos de Tipo Kaurano/química , Fase G2/efectos de los fármacos , Glucósidos/química , Neoplasias/metabolismo , Profármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Catálisis , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/aislamiento & purificación , Diterpenos de Tipo Kaurano/farmacología , Células HCT116 , Células Hep G2 , Humanos , Resinas de Intercambio Iónico , Neoplasias/tratamiento farmacológico , Profármacos/síntesis química , Profármacos/química , Profármacos/aislamiento & purificación , Profármacos/farmacologíaRESUMEN
Covering: 2010 to 2020This review article describes how cationic rearrangement reactions have been used in natural product total synthesis over the last decade as a case study for the many productive ways by which isomerization reactions are enabling for synthesis. This review argues that isomerization reactions in particular are well suited for computational evaluation, as relatively simple calculations can provide significant insight.
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Productos Biológicos/química , Benzofuranos/síntesis química , Benzofenonas/síntesis química , Benzoquinonas/síntesis química , Productos Biológicos/síntesis química , Cationes , Ciclización , Diterpenos de Tipo Kaurano/síntesis química , Alcaloides Indólicos/síntesis química , Isomerismo , Triterpenos Pentacíclicos/síntesis química , Sesquiterpenos/química , Estilbenos/síntesis química , Terpenos/síntesis químicaRESUMEN
Several glycoconjugates of the diterpenoid isosteviol (16-oxo-ent-beyeran-19-oic acid) with a 1,2,3-triazolyl moiety were synthesized, and their cytotoxicity was evaluated against some human cancer and normal cell lines. Most of the synthesized compounds demonstrated weak inhibitory activities against the M-HeLa and MCF-7 human cancer cell lines. Three lead compounds, 54, 56 and 57, exhibited high selective cytotoxic activity against M-HeLa cells (IC50 = 1.7-1.9 µM) that corresponded to the activity of the anticancer drug doxorubicin (IC50 = 3.0 µM). Moreover, the lead compounds were not cytotoxic with respect to a Chang liver human normal cell line (IC50 > 100 µM), whereas doxorubicin was cytotoxic to this cell line (IC50 = 3.0 µM). It was found that cytotoxic activity of the lead compounds is due to induction of apoptosis proceeding along the mitochondrial pathway. The present findings suggest that 1,2,3-triazolyl-ring-containing glycoconjugates of isosteviol are a promising scaffold for the design of novel anticancer agents.
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Diterpenos de Tipo Kaurano/síntesis química , Glicoconjugados/química , Glicósidos/química , Triazoles/química , Apoptosis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura MolecularRESUMEN
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.
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Antineoplásicos/farmacología , Diterpenos de Tipo Kaurano/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The readily available natural product stevioside provides a unique diterpene core structure that can be explored for small molecule library development by diversity-oriented synthesis and functional group transformations. Validation arrays were prepared from steviol, isosteviol, and related analogues, derived from stevioside, to produce over 90 compounds. These compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for screening in the Molecular Libraries Screening Center Network. Micromolar hits were identified in multiple high-throughput assays for several library members. A cheminformatics analysis of the compounds was performed that verified the expected diversity and complexity of this set of compounds. The screening results indicate that scaffolds-derived natural products can provide screening hits against multiple target proteins.