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1.
Nature ; 584(7819): 75-81, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760044

RESUMO

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3-6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C-H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon-nitrogen (C-N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C-N coupling protocol by preparing commercial medicines and by the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.


Assuntos
Compostos de Anilina/síntese química , Hidrogênio/química , Processos Fotoquímicos , Aminação , Aminas/química , Compostos de Anilina/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise/efeitos da radiação , Cicloexanonas/química , Oxirredução/efeitos da radiação , Processos Fotoquímicos/efeitos da radiação , Esteroides/síntese química , Esteroides/química , Terpenos/síntese química , Terpenos/química
2.
Pain Physician ; 23(4): E417-E424, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32709188

RESUMO

BACKGROUND: Epidural steroid injection (ESI) is a common practice for pain treatment since 1953. In 2014, the FDA issued a warning about ESI. Studies have focused on the effect of the particle size and their ability to generate harmful aggregates. Although steroid aggregates provide longer times for reabsorption, therefore a longer anti-inflammatory effect, they are potentially harmful to the central nervous system via embolic mechanisms.Previous studies have established that steroidal aggregates with asizes over 100 mu m are potentially able to occlude blood vessels. Studies by Tiso et al and Benzon et al addressed the role of steroids on CNS adverse events, with similar outcomes. The main difference was on the role of aggregates with a size over 100 mu m, which Benzon et al. attributed to the ability of certain steroid preparations to rapidly precipitate and form large aggregates. OBJECTIVES: Studying the effect of the time elapsed between mixing the steroid preparation and injection on the number and size of aggregates with sizes above 100 mu m. STUDY DESIGN: Original study in basic science. SETTING: Basic scienceMETHODS: Steroids evaluated are commonly used in Spain for ESI: betamethasone, triamcinolone, and dexamethasone. The size and number of the aggregates was determined for undiluted commercial steroid preparations in the usual amount for a single and double dosage used for ESI.Samples were examined with a Leica TCS-SP2 microscope at the first, the fifth and the 30th minute after shaking the preparations. Aggregates observed in the different preparations were manually counted and grouped in the following size range: 0-20, 20-50, 50-100, 100-300, 300-500 and > 500 mu m.Statistical analysis was carried out using the R software. Nonparametric techniques were used in the comparison of aggregate size. Global comparison of the groups using the Kruskal-Wallis test and post-hoc comparisons using the Wilcoxon test, adjusting P-values by the Holm method for multiple comparisonsRESULTS: Aggregates present in triamcinolone and betamethasone samples were statistically larger than in dexamethasone samples. Triamcinolone suspensions produced significantly larger aggregates than betamethasone five minutes after mixing. Triamcinolone preparations produced greater particle aggregates (> 500 mu m), which were not present in dexamethasone and betamethasone preparations. LIMITATIONS: Study how the human internal factors like blood elements and spinal fluid could interact with steroids and influence the size of the aggregates formed. CONCLUSIONS: This study demonstrates that the size of the particles injected depends on the type of steroid and the time allowed between mixing and injecting. The results demonstrate that waiting longer than 5 minutes between mixing and injecting can predispose the formation of potentially harmful aggregates in triamcinolone and betamethasone samples. The presence of greater particle aggregates (> 500 mu m) may occlude some important vessels and arteries with serious adverse results. Vigorous shaking of the injectable could prevent such events. KEY WORDS: Epidural steroid injection, triamcinolone, betamethasone, dexamethasone, steroid aggregates.


Assuntos
Tamanho da Partícula , Esteroides/administração & dosagem , Esteroides/química , Betametasona/administração & dosagem , Betametasona/química , Dexametasona/administração & dosagem , Dexametasona/química , Glucocorticoides/administração & dosagem , Glucocorticoides/química , Humanos , Injeções Epidurais/métodos , Microscopia/métodos , Triancinolona/administração & dosagem , Triancinolona/química
3.
Food Chem ; 333: 127430, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679413

RESUMO

Phytosterols (PS) are a group of sterols distributed in foods and plants, where it is prone to oxidation. In this work, we studied the reaction mechanism of phytosterols, using density functional theory (DFT) calculation and experimental methods to study the photooxidation of phytosterols. Under LED light illumination, experimental photooxidation of these phytosterols gives rise to the prior three kind oxides of phytosterol: 6α-OH, 7α-OH, and 7ß-OH. The mechanistic investigations by DFT suggest that singlet oxygen (1O2)-mediated photooxidation (Type II mechanism) generated radical adds to the C5 and C6 on the B Ring of steroid nucleus and reaction in C7 initiated from C5 products through rearrangement pathway. Furthermore, the stereoselectivity at C5, C6 and C7 provides a mechanistic guide for phytosterols photooxidation. These efforts are expected to serve as an essential exploratory study for the oxidation mechanism of phytosterols in the complex food matrix and antioxidation technology for phytosterols.


Assuntos
Processos Fotoquímicos , Fitosteróis/química , Alcenos/química , Teoria da Densidade Funcional , Hidrogênio/química , Luz , Oxidantes Fotoquímicos/química , Oxirredução , Óxidos/química , Esteroides/química
4.
J Chromatogr A ; 1624: 461231, 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32540072

RESUMO

Detection of endogenous anabolic androgenic steroids (EAAS) misuse is a major challenge in doping control analysis. Currently, a number of endogenous steroids, which constitute the steroid profile, are quantified using gas chromatography (GC). With this methodology, only the sum of the free and glucuronidated steroids is measured together. A dilute-and-shoot LC-MS method, which is compliant with the quality requirements for measuring EAAS established by the World Anti-Doping Agency (WADA), was developed and validated containing glucuronidated and sulfated steroids in order to gain some extra information and to expand the existing steroid profile. The developed method is, to the best of our knowledge, the first method to combine both steroid glucuronides and sulfates, which is compliant with the quality standards of the technical document on EAAS, established by WADA. The first advantage of this new steroid profile is the reduced sample preparation time, as it is a direct injection method of diluted urine. A second advantage is the ability of the used gradient to separate 5α-androstane-3α,17ß-diol-3-glucuronide (5ααßdiol3G), 5α-androstane-3α,17ß-diol-17-glucuronide (5ααßdiol17G), 5ß-androstane-3α,17ß-diol-3-glucuronide (5ßαßdiol3G) and 5ß-androstane-3α,17ß-diol-17-glucuronide (5ßαßdiol17G) allowing to gain specific information on these isomers, which cannot be accomplished in GC-MS screening due to hydrolysis. This steroid profile also contains free testosterone, 5α-androstane-3,17-dione and 5ß-androstane-3,17-dione as markers of degradation. In total, 17 compounds and 10 isotopically labelled internal standards are included in this method.


Assuntos
Esteroides/urina , Cromatografia Líquida de Alta Pressão , Doping nos Esportes , Glucuronídeos/análise , Glucuronídeos/química , Glucuronídeos/urina , Humanos , Espectrometria de Massas , Esteroides/química
5.
Ecotoxicol Environ Saf ; 196: 110586, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32272348

RESUMO

Manure fertilization and wastewater irrigation can introduce the biologically potent synthetic progestins into agricultural soils, causing endocrine disruption in organisms of nearby surface waters. Therefore, this study investigated the sorption and desorption potential of etonogestrel, medroxyprogesterone, gestodene, norgestrel, cyproterone acetate, levonorgestrel, and dienogest in five agricultural soil-water systems. Sorption data were well-described by the linear sorption model. In most batch systems, cyproterone acetate exhibited the highest affinities for soils, followed by etonogestrel, medroxyprogesterone, levonorgestrel, gestodene, norgestrel, and dienogest. The sorption magnitudes (logKoc or logKd) were significantly correlated with the progestin hydrophobicities (R2 = 0.72-0.86, p < 0.05). The Kd values of the progestins were also significantly correlated with organic carbon content and pore volumes of the soils (R2 = 0.68-0.98, p < 0.05). In addition, 0.5 M urea resulted in 3-19% decreases in Kd values of the progestins. Taken together, these data indicated that hydrophobic partitioning interaction, hydrogen bonding interaction, and pore filling were the sorption mechanisms for the progestins in soil-water systems. No significant desorption hysteresis was observed for the progestins, indicating that they can be readily desorbed under rainfall or irrigation events. Based on the sorption and desorption data, we estimated the dynamic transport of the progestins in conventional agricultural management systems, and predicted the concentrations of the progestins as a function of soil-sorbed concentration, water-soil ratio, and dilution factor of receiving waters. This study will improve the understanding of the risks posed by the progestins under field-scale hydrological conditions.


Assuntos
Congêneres da Progesterona/química , Poluentes do Solo/química , Solo/química , Esteroides/química , Águas Residuárias/química , Adsorção , Irrigação Agrícola , Esterco/análise , Congêneres da Progesterona/análise , Poluentes do Solo/análise , Esteroides/análise
6.
Molecules ; 25(6)2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32204362

RESUMO

The detailed chemical analysis of the methanol extract of Meripilus giganteus (Pers.) P. Karst. led to the isolation of two new cerebrosides, mericeramides A (1) and B (2) together with cerebroside B (3), ergosterol (4), 3ß-hydroxyergosta-7,22-diene (5), cerevisterol (6), 3ß-hydroxyergosta-6,8(14),22-triene (7), 3ß-O-glucopyranosyl-5,8-epidioxyergosta-6,22-diene (8) and (11E,13E)-9,10-dihydroxy-11,13-octadecadienoic acid (9). The structures of the compounds were determined on the basis of NMR and MS spectroscopic analysis. Mericeramide A (1) is the first representative of halogenated natural cerebrosides. The isolated fungal metabolites 1-9 were evaluated for their antioxidant activity using the oxygen radical absorbance capacity (ORAC) assay. Compounds 2, 5 and 9 proved to possess considerable antioxidant effects, with 2.50 ± 0.29, 4.94 ± 0.37 and 4.27 ± 0.05 mmol TE/g values, respectively. The result obtained gives a notable addition to the chemical and bioactivity profile of M. giganteus, highlighting the possible contribution of this species to a versatile and balanced diet.


Assuntos
Agaricales/química , Antioxidantes/análise , Cerebrosídeos/análise , Esteroides/análise , Antioxidantes/química , Cerebrosídeos/química , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Capacidade de Absorbância de Radicais de Oxigênio , Esteroides/química
7.
Int J Mol Sci ; 21(5)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121303

RESUMO

BACKGROUND: Increasingly, different heterocyclic systems have been introduced into the steroid nucleus to significantly enhance the antitumor activities of steroid molecules. However, in this study, few literature precedents describing the pyrazine heterocyclic-condensed modification to an A-ring of steroid monomers were found, although the pyrazine group is thought to be essential for the potent anticancer activity of clinically relevant drugs and natural steroid dimers. METHODS AND RESULTS: Two series of novel A-ring fused steroidal pyrazines were designed and efficiently synthesized from commercially available progesterone via key α-ketoenol intermediates. Through a cell counting kit-8 cytotoxic assay of 36 derivatives for three tumor cells, 14 compounds displayed significant antiproliferative activity compared to 5-fluorouracil, especially for human prostatic tumor cells (PC-3) in vitro. Further mechanistic studies indicated that the most active compound, 12n (IC50, 0.93 µM; SI, 28.71), could induce the cell apoptosis of PC-3 cells in a dose-dependent manner and cause cell cycle arrest in the G2/M phase. The molecular docking study suggested that compound 12n fitted the active sites of cytochrome P450 17A1 (6CIZ) well. CONCLUSIONS: 12n might serve as a promising lead compound for the development of novel anticancer drugs. This facile ring-closing strategy may provide a novel and promising avenue for the cycloaddition reaction of the steroidal skeleton through α-ketoenol intermediates.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Pirazinas/síntese química , Pirazinas/farmacologia , Esteroides/síntese química , Esteroides/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Pirazinas/química , Esteroides/química , Relação Estrutura-Atividade
8.
J Chromatogr A ; 1620: 460989, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32151414

RESUMO

A GC-MS based analytical method was developed for the profiling of oil-based AAS products using 15 organic constituents as target compounds. A total of 219 compounds were identified in 109 seized AAS products, among them 15 target compounds were selected. The selection was based on each compound's occurrence, reproducibility, and variance between products. The 15 target compounds did not include the active steroid itself, but only compounds found in the carrier oil. The subsequent method validation included assessment of specificity, linearity, precision, robustness and sample stability. The method was finally applied for the classification of a set of 27 seizures of AAS products supplied by the police. The classification was based on the Pearson correlation coefficient using pre-treated peak area data from the 15 target compounds. A successful classification was obtained, with only a small overlap between linked and unlinked samples. A 1% false-positive rate could be obtained at a threshold of 0.625 in terms of the Pearson distance. The present study thus demonstrates that it is possible to profile and classify AAS products with regard to a common origin. As the profiling method is not specific with regards to the steroid content, it may potentially be used to profile and compare other kinds of oil-based liquids.


Assuntos
Anabolizantes/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Óleos/química , Esteroides/análise , Anabolizantes/química , Humanos , Reprodutibilidade dos Testes , Esteroides/química
9.
Chem Pharm Bull (Tokyo) ; 68(3): 273-287, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115535

RESUMO

Phytochemical analysis of the whole Helleborus foetidus plants identified 28 steroidal glycosides (1-28), including 20 novel spirostanol glycosides (1-20) and a novel furostanol glycoside (21). The structures of the newly identified compounds were elucidated by two-dimensional NMR spectroscopy and hydrolytic cleavage. Compounds 12, 13, and 15 were determined to be spirostanol trisdesmosides bearing sugar moieties at the C-1, -21, and -24 hydroxy groups of the aglycone unit. The isolated compounds were subsequently evaluated for cytotoxic activity against HL-60 human promyelocytic leukemia cells and A549 human lung carcinoma cells. In particular, 7 showed cytotoxic activity against the HL-60 and A549 cells, with IC50 values of 5.9 and 6.6 µM, respectively, whereas 19 was selectively cytotoxic to A549 cells with an IC50 value of 5.5 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Glicosídeos/farmacologia , Helleborus/química , Compostos Fitoquímicos/farmacologia , Esteroides/farmacologia , Células A549 , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/química , Glicosídeos/isolamento & purificação , Células HL-60 , Humanos , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Esteroides/química , Esteroides/isolamento & purificação , Relação Estrutura-Atividade
10.
Artigo em Inglês | MEDLINE | ID: mdl-32109748

RESUMO

The standard approach to detect misuse with testosterone in sport is based on the determination and evaluation of the urinary steroid profile followed by the confirmation of atypical profiles using isotope ratio mass spectrometry. The detection capacity of these methods can be attenuated by confounding factors or testosterone preparations with endogenous isotopic fingerprints. An alternative detection method for misuse of an endogenous steroid in sports is the direct detection of the administered steroid ester present in most preparations. Thus unambiguous proof for doping misuse can be delivered. In this work, the sensitivity of gas chromatography coupled to a triple quadrupole with chemical ionization (GC-CI-MS/MS) is applied to detect trace levels of 10 testosterone and 2 nandrolone esters in plasma for in human doping analysis. The detection method was developed employing a liquid-liquid extraction and HPLC cleanup step before analysis on the GC-CI-MS/MS. The quantitative method was validated in a linear range of 100-2000 pg/ml and proved to be selective, reproducible and very sensitive with limits of detection as low as to 10 pg/ml. A clinical study with the administration of testosterone undecanoate in 3 volunteers was carried out and the compound was detectable up to 86 days after administration.


Assuntos
Doping nos Esportes , Cromatografia Gasosa-Espectrometria de Massas/métodos , Esteroides/sangue , Espectrometria de Massas em Tandem/métodos , Ésteres , Humanos , Modelos Lineares , Extração Líquido-Líquido , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Esteroides/química , Esteroides/isolamento & purificação , Testosterona/análogos & derivados , Testosterona/sangue
11.
Chemistry ; 26(19): 4256-4260, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32031278

RESUMO

We report the first chemical synthesis of eurysterol A, a cytotoxic and antifungal marine steroidal sulfate with a unique C8-C19 oxy-bridged cholestane skeleton. After C19 hydroxylation of cholesteryl acetate, used as an inexpensive commercial starting material, the challenging oxidative functionalization of ring B was achieved by two different routes to set up a 5α-hydroxy-7-en-6-one moiety. As a key step, an intramolecular oxa-Michael addition was exploited to close the oxy-bridge (8ß,19-epoxy unit). DFT calculations show this reversible transformation being exergonic by about -30 kJ mol-1 . Along the optimized (scalable) synthetic sequence, the target natural product was obtained in only 11 steps in 5 % overall yield. In addition, an access to (isomeric) 7ß,19-epoxy steroids with a previously unknown pentacyclic ring system was discovered.


Assuntos
Antifúngicos/síntese química , Esteroides/química , Esteróis/síntese química , Antifúngicos/química , Hidroxilação , Isomerismo , Estrutura Molecular , Oxirredução , Esteróis/química
12.
Nat Commun ; 11(1): 654, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005831

RESUMO

The taccalonolide microtubule stabilizers covalently bind ß-tubulin and overcome clinically relevant taxane resistance mechanisms. Evaluations of the target specificity and detailed drug-target interactions of taccalonolides, however, have been limited in part by their irreversible target engagement. In this study, we report the synthesis of fluorogenic taccalonolide probes that maintain the native biological properties of the potent taccalonolide, AJ. These carefully optimized, cell-permeable probes outperform commercial taxane-based probes and enable direct visualization of taccalonolides in both live and fixed cells with dramatic microtubule colocalization. The specificity of taccalonolide binding to ß-tubulin is demonstrated by immunoblotting, which allows for determination of the relative contribution of key tubulin residues and taccalonolide moieties for drug-target interactions by activity-based protein profiling utilizing site-directed mutagenesis and computational modeling. This combinatorial approach provides a generally applicable strategy for investigating the binding specificity and molecular interactions of covalent binding drugs in a cellular environment.


Assuntos
Microtúbulos/química , Esteroides/química , Linhagem Celular Tumoral , Humanos , Cinética , Microtúbulos/metabolismo , Modelos Moleculares , Esteroides/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
13.
J Steroid Biochem Mol Biol ; 199: 105586, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31926269

RESUMO

Recent studies have shown that an adrenal steroid 11ß-hydroxy-4-androstene-3,17-dione serves as the precursor to androgens, 11-ketotestosterone and 11-ketodihydrotestosterone (11KDHT). The biosynthetic pathways include the reduction of 3- and 17-keto groups of the androgen precursors 11-keto-C19-steroids, which has been reported to be mediated by three human enzymes; aldo-keto reductase (AKR)1C2, AKR1C3 and 17ß-hydroxysteroid dehydrogenase (HSD) type-3. To explore the contribution of the enzymes in the reductive metabolism, we kinetically compared the substrate specificity for 11-keto-C19-steroids among purified recombinant preparations of four AKRs (1C1, 1C2,1C3 and 1C4) and DHRS11, which shows 17ß-HSD activity. Although AKR1C1 did not reduce the 11-keto-C19-steroids, AKR1C3 and DHRS11 reduced 17-keto groups of 11-keto-4-androstene-3,17-dione, 11-keto-5α-androstane-3,17-dione (11K-Adione) and 11-ketoandrosterone with Km values of 5-28 µM. The 3-keto groups of 11KDHT and 11K-Adione were reduced by AKR1C4 (Km 1 µM) more efficiently than by AKR1C2 (Km 5 and 8 µM, respectively). GC/MS analysis of the products showed that DHRS11 acts as 17ß-HSD, and that AKR1C2 and AKR1C4 are predominantly 3α-HSDs, but formed a minor 3ß-metabolite from 11KDHT. Since DHRS11 was thus newly identified as 11-keto-C19-steroid reductase, we also investigated its substrate-binding mode by molecular docking and site-directed mutagenesis of Thr163 and Val200, and found the following structural features: 1). There is a space that accommodates the 11-keto group of the 11-keto-C19-steroids in the substrate-binding site. 2) Val200 is a critical determinant for exhibiting the strict 17ß-HSD activity of the enzyme, because the Val200Leu mutation resulted in both significant impairment of the 17ß-HSD activity and emergence of 3ß-HSD activity towards 5α-androstanes including 11KDHT.


Assuntos
17-Hidroxiesteroide Desidrogenases/química , 20-Hidroxiesteroide Desidrogenases/química , Aldo-Ceto Redutases/química , Esteroides/biossíntese , 17-Hidroxiesteroide Desidrogenases/genética , 17-Hidroxiesteroide Desidrogenases/metabolismo , 20-Hidroxiesteroide Desidrogenases/genética , 20-Hidroxiesteroide Desidrogenases/metabolismo , Membro C3 da Família 1 de alfa-Ceto Redutase/química , Membro C3 da Família 1 de alfa-Ceto Redutase/genética , Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Aldo-Ceto Redutases/genética , Aldo-Ceto Redutases/metabolismo , Androgênios/biossíntese , Androgênios/química , Vias Biossintéticas/genética , Humanos , Simulação de Acoplamento Molecular , Oxirredutases/química , Oxirredutases/genética , Oxirredutases/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Esteroides/química , Especificidade por Substrato , Testosterona/análogos & derivados , Testosterona/metabolismo
14.
J Steroid Biochem Mol Biol ; 199: 105592, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31953168

RESUMO

In the plant kingdom, steroidal lactones occur as glycosides, compounds consisting of a sugar moiety linked to a steroid aglycone. Steroidal lactones consist of five fused rings, with a total of 22 carbon atoms. Numerous methods for the preparation of steroidal lactones take advantage of the fact that steroid spirostanes may be degraded from six- to a five-rings structure. One of the most striking features common to reactions of steroid sapogenins is the C22-lactone formation. In the review, different methods for the preparation of steroidal lactones are presented with consideration of the structure of starting material. In addition, examples of lactones used in the synthesis of biologically active compounds and their analogues are described.


Assuntos
Glicosídeos/química , Lactonas/química , Esteroides/química , Radioisótopos de Carbono/química , Estrutura Molecular , Sapogeninas/química , Espirostanos/química , Esteroides/biossíntese
15.
Biomed Chromatogr ; 34(4): e4794, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31944362

RESUMO

Just as natural saponins transform into aglycones, secondary glycosides and their derivatives using biotransformation technology, steroidal saponins may also undergo similar transformation after stir-frying. The purpose of this study was to elucidate the variations and the reasons for these variations in the contents of steroidal saponins in Fructus Tribuli (FT) during a stir-frying treatment. Stir-fried FT was processed in different time-temperature conditions. An UHPLC-MS/MS method was established and fully validated for quantitative analysis. In addition, the simulation processing products of tribuluside A, terrestroside B, terrestrosin K, terrestrosin D and 25R-tribulosin were determined by qualitative analysis using UHPLC-Q-TOF-MS. The established UHPLC-MS/MS method provides a rapid, flexible, and reliable method for the quality assessment of FT. The present study revealed that furostanol saponins with a C22-OH group could transform into corresponding furostanol saponins with a C-20-C-22 double bond (FSDB) via dehydroxylation. Additionally, FSDB could be successively converted into its secondary glycosides via a deglycosylation reaction. The transformation of spirostanol saponins into corresponding aglycones via deglycosylation led to a decrease in spirostanol saponins and an increase in aglycones. The results of this research provided scientific evidence of variation and structural transformation among steroidal saponins. These findings might be helpful for elucidating the processing mechanism of FT.


Assuntos
Culinária/métodos , Frutas/química , Saponinas/análise , Esteroides/análise , Tribulus/química , Glicosídeos/análise , Limite de Detecção , Modelos Lineares , Medicina Tradicional Chinesa , Reprodutibilidade dos Testes , Saponinas/química , Esteroides/química
16.
Nat Prod Res ; 34(8): 1097-1104, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30616378

RESUMO

A new 22,26-seco physalin, physalin XI (1) together with 5 known compounds, were isolated from the dichloromethane extract of Physalis angulata L. The structure of isolated compounds was elucidated by spectroscopic analysis. The effects of isolated compounds on in vitro cytotoxicity were investigated. Compound 1 was assessed for its cytotoxicity against cancer cell lines (HepG2, HeLa, HuCCA-1, T47-D and A-549) and a normal cell line (MRC-5), and the result showed that it has no activity. Compounds 2 and 4 are highly toxic to H69AR and MDA-MB-23 cell lines. This property appears to be related to the presence of their conjugated double bond or epoxy groups and is a more reliable indication of toxicity than substitution on C(5)-C(6).


Assuntos
Physalis/química , Secoesteroides/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Extratos Vegetais/química , Secoesteroides/química , Esteroides/química , Esteroides/isolamento & purificação , Relação Estrutura-Atividade
17.
J Chromatogr A ; 1614: 460709, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31784081

RESUMO

Steroid hormones are a type of crucial substances that mediate numerous vital physiological functions. The comprehensive detection of steroid hormones can help understand the physiopathologic mechanism of steroid hormone-related diseases. It is very difficult to determine steroid hormones in biological samples due to their low endogenous concentrations and poor ionization efficiency. In this study, an efficient and sensitive approach was developed for profiling steroid hormones by combining liquid-liquid extraction and parallel derivatization with liquid chromatography-tandem mass spectrometry. Methoxyamine and dansyl chloride were used to derivatize steroid hormones containing carbonyl and phenolic hydroxyl groups, respectively. Our established method achieved simultaneous analysis of carbonyl and phenolic hydroxyl-containing steroid hormones and could cover estrogens, androgens, corticoids and progestogens. Twenty-nine steroid hormones were detected at pg/mL levels with the sensitivity enhanced by three orders of magnitude after derivatization. The linearity (with linear range of 2-4 orders of magnitude), precision (less than 15%) and recovery (71.1-128.7%) were satisfactory for quantitative analysis of steroid hormones. Finally, the established method was successfully employed to the determination of steroid hormones in serum samples of healthy males and females as well as ovarian cancer patients. The results showed that this approach was suitable and reliable for routine test of steroid hormones containing carbonyl and phenolic hydroxyl groups.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Esteroides/química , Compostos de Dansil/química , Feminino , Humanos , Extração Líquido-Líquido , Masculino , Metoxamina/química , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Progestinas/sangue , Progestinas/química , Progestinas/isolamento & purificação , Esteroides/sangue , Esteroides/isolamento & purificação
18.
Future Med Chem ; 12(1): 19-35, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31729254

RESUMO

Aim: Steroidal prodrugs of nitrogen mustards such as estramustine and prednimustine have proven effective anticancer agents in clinical use since the 1970s. In this work, we aimed to develop steroidal prodrugs of the novel nitrogen mustard POPAM-NH2. POPAM-NH2 is a melphalan analogue that was coupled with three different steroidal lactams. Methodology: The new conjugates were preclinically tested for anticancer activity against nine human and one rodent cancer experimental models, in vitro and in vivo. Results & conclusion: All the steroidal alkylators showed high antitumor activity, in vitro and in vivo, in the experimental systems tested. Moreover, these hybrid compounds showed by far superior anticancer activity compared with the alkylating agents, melphalan and POPAM-NH2.


Assuntos
Mostarda de Anilina/análogos & derivados , Antineoplásicos/farmacologia , Descoberta de Drogas , Lactamas/farmacologia , Propionatos/farmacologia , Esteroides/farmacologia , Mostarda de Anilina/administração & dosagem , Mostarda de Anilina/química , Mostarda de Anilina/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HT29 , Humanos , Injeções Intraperitoneais , Lactamas/administração & dosagem , Lactamas/química , Masculino , Camundongos , Camundongos SCID , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Propionatos/administração & dosagem , Propionatos/química , Esteroides/administração & dosagem , Esteroides/química , Relação Estrutura-Atividade
19.
J Chromatogr A ; 1612: 460661, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-31708215

RESUMO

Untargeted steroid identification represents a great analytical challenge even when using sophisticated technology such as two-dimensional gas chromatography coupled to high resolution mass spectrometry (GC × GCHRMS) due to the chemical similarity of the analytes. Moreover, when analytical standards, mass spectral and retention index databases are not available, compound annotation is cumbersome. Hence, there is a need for the development of retention time prediction models in order to explore new annotation approaches. In this work, we evaluated the use of several in silico methods for retention time prediction in multidimensional gas chromatography. We use three classical machine learning (CML) algorithms (Partial Least Squares (PLS), Support Vector Regression (SVR) and Random Forest Regression (RFR)) and two deep learning approaches (dense neural network (DNN) and three-dimensional convolutional neural network (CNN)). Whereas molecular descriptors were utilized for the CLM and DNN algorithms, three-dimensional molecular representation based on the electrostatic potential (ESP) was studied as input data as is for the CNN. All the developed models showed similar performances with Q2 values over 0.9. However, among all CNN showed the best performance, resulting in average retention time prediction errors of 2% and 6% for the first and second separation dimension, respectively. Additionally, only the three-dimensional ESP representation coupled with CNN was able to extract the stereochemical information crucial for the separation of diastereomers. The combination of retention time prediction and high-resolution mass spectral data applied to clinical samples enabled the untargeted annotation of 12 steroid metabolites in the urine of new-borns.


Assuntos
Aprendizado Profundo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Esteroides/análise , Análise dos Mínimos Quadrados , Redes Neurais de Computação , Eletricidade Estática , Esteroides/química , Máquina de Vetores de Suporte
20.
Eur J Med Chem ; 187: 111909, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31830636

RESUMO

Hybrid chemical compounds formed by conjugation of two or more bioactive molecules have shown wide variety of applications in biology, microelectronics as well as material sciences. In particular, the conjugates of steroid framework are known to have broad biological activity profile due to their ability to penetrate the biomembranes and bind to specific hormone receptors. Among the various conjugates of steroids, Steroid Amino Acid Conjugates (SAACs) are attractive because of the possibility of fine tuning of the amphiphilicity with position, orientation and nature of amino acids. The structural details, applications, mechanistic insights and their diverse pharmacological as well as other physicochemical properties of several SAACs are summarized in the present review. This review provides better insight for medicinal chemists to design and explore such novel conjugates which can be used as lead structures in the future drug discovery or as probes to understand the complex biological system.


Assuntos
Aminoácidos/farmacologia , Esteroides/farmacologia , Aminoácidos/química , Animais , Humanos , Conformação Molecular , Esteroides/química
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