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1.
PLoS One ; 15(8): e0236879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790676

RESUMO

Benign prostatic hyperplasia (BPH) is a progressive pathological condition associated with proliferation of prostatic tissues, prostate enlargement, and lower-urinary tract symptoms. However, the mechanism underlying the pathogenesis of BPH is unclear. The aim of this study was to investigate the protective effects of a combination of Stauntonia hexaphylla and Cornus officinalis (SC extract) on a testosterone propionate (TP)-induced BPH model. The effect of SC extract was examined in a TP-induced human prostate adenocarcinoma cell line. Male Sprague-Dawley rats were randomly divided into 5 groups (n = 6) for in vivo experiments. To induce BPH, all rats, except those in the control group, were administered daily with subcutaneous injections of TP (5 mg/kg) and orally treated with appropriate phosphate buffered saline/drugs (finasteride/saw palmetto/SC extract) for 4 consecutive weeks. SC extract significantly downregulated the androgen receptor (AR), prostate specific antigen (PSA), and 5α-reductase type 2 in TP-induced BPH in vitro. In in vivo experiments, SC extract significantly reduced prostate weight, size, serum testosterone, and dihydrotestosterone (DHT) levels. Histologically, SC extract markedly recovered TP-induced abnormalities and reduced prostatic hyperplasia, thereby improving the histo-architecture of TP-induced BPH rats. SC extract also significantly downregulated AR and PSA expression, as assayed using immunoblotting. Immunostaining revealed that SC extract markedly reduced the 5α-reductase type 2 and significantly downregulated the expression of proliferating cell nuclear antigen. In addition, immunoblotting of B-cell lymphoma 2 (Bcl-2) family proteins indicated that SC extract significantly downregulated anti-apoptotic Bcl-2 and markedly upregulated pro-apoptotic B cell lymphoma-associated X (Bax) expression. Furthermore, SC treatment significantly decreased the Bcl-2/Bax ratio, indicating induced prostate cell apoptosis in TP-induced BPH rats. Thus, our findings demonstrated that SC extract protects against BPH by inhibiting 5α-reductase type 2 and inducing prostate cell apoptosis. Therefore, SC extract might be useful in the clinical treatment of BPH.


Assuntos
Apoptose/efeitos dos fármacos , Colestenona 5 alfa-Redutase/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/prevenção & controle , Substâncias Protetoras/uso terapêutico , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Cornus/química , Cornus/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Folhas de Planta/metabolismo , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/etiologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ranunculales/química , Ranunculales/metabolismo , Ratos , Ratos Sprague-Dawley , Propionato de Testosterona/efeitos adversos
2.
Molecules ; 25(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033281

RESUMO

This work describes the utility of pyrazole-4-carbaldehyde 1 as starting material for the synthesis of a novel potent series of 5α-reductase and aromatase inhibitors derived from 1,2,3-triazole derivative. Condensation of 1 with active methylene and different amino pyrazoles produced the respective Schiff bases 2-4, 8 and 9. On the other hand, 1 was reacted with ethyl cyanoacetate and thiourea in one-pot reaction to afford the pyrazolo-6- thioxopyridin-2-[3H]-one (10). Moreover, α-ß unsaturated chalcone derivative 11 was prepared via the reaction of compound 1 with P-methoxy acetophenone, which in turn reacted with each of ethyl cyanoacetate, malononitrile, hydrazine hydrate, and thiosemicarbazide to afford the corresponding pyridine and pyrazole derivatives 13, 14, 17, and 20. The structure of newly synthesized compounds was characterized by analytical and spectroscopic data (IR, MS and NMR). All new compounds were evaluated against 5α-reductase and aromatase inhibitors and the results showed that many of these compounds inhibit 5α-reductase and aromatase activity; compound 13 was found to be the highest potency among the tested samples comparing with the reference drugs.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Triazóis/química , Inibidores de 5-alfa Redutase/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Aromatase/efeitos dos fármacos , Inibidores da Aromatase/química , Colestenona 5 alfa-Redutase/efeitos dos fármacos , Di-Hidrotestosterona/sangue , Letrozol/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Testosterona/sangue
3.
J Enzyme Inhib Med Chem ; 34(1): 1597-1606, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31469015

RESUMO

Prostate cancer (PCa) is the second leading cause of death in men. Apart from androgen receptor, 5α-reductase has also been recognized as a potential target. In this study, a series of androst-17ß-amide compounds have been designed and synthesized targeting both AR and 5α-reductase. Their anti-proliferation activities were evaluated in AR + cell line 22RV1 and AR - cell line PC-3. The results indicated that most of the synthesized compounds inhibited the testosterone-stimulated cell proliferation with good selectivity and safety. Among all the compounds, androst[3,2-c]pyrazole derivatives (9a-9d) displayed the best inhibition activity comparable with flutamide. Moreover, most of the synthesized compounds displayed good 5α-reductase inhibitory activities with IC50 lower than 1 µM. The docking result of 9d-AR indicated that AR was forced to expands its binding cavity and maintain an antagonistic conformation since the steric hindrance of 9d impeded H12 transposition. Overall, compound 9d can be identified as a potential dual 5α-reductase inhibitor and AR antagonist, which might be of therapeutic importance for PCa treatment.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Androstenos/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Desenho de Fármacos , Receptores Androgênicos/metabolismo , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Androstenos/síntese química , Androstenos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Células PC-3 , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Fitoterapia ; 133: 102-108, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30605780

RESUMO

Gossypol is a yellow polyphenol isolated from cotton seeds. It has the antitumor activity and it is being tested to treat prostate cancer. However, its underlying mechanisms are still not well understood. The present study investigated the inhibitory effects of gossypol acetate on rat 5α-reductase 1, 3α-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 for androgen metabolism. Rat 5α-reductase 1, 3α-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 were expressed in COS-1 cells. Immature Leydig cells that contain these enzymes were isolated from 35-day-old male Sprague Dawley rats. The potency and mode of action of gossypol acetate to inhibit these enzymes in both enzyme-expressed preparations and immature Leydig cells were examined. Molecular docking study of gossypol on the crystal structure of 3α-hydroxysteroid dehydrogenase was performed. Gossypol acetate inhibited 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase with IC50 values of 3.33 ±â€¯0.07 and 0.52 ±â€¯0.06 × 10-6 M in the expressed enzymes as well as 8.512 ±â€¯0.079 and 1.032 ±â€¯0.068 × 10-6 M in intact rat immature Leydig cells, respectively. Gossypol acetate inhibited rat 5α-reductase 1 in a noncompetitive mode and 3α-hydroxysteroid dehydrogenase in a mixed mode when steroid substrates were supplied. Gossypol acetate weakly inhibited retinol dehydrogenase 2 with IC50 value over 1 × 10-4 M. Molecular docking analysis showed that gossypol partially bound to the steroid-binding site of the crystal structure of rat 3α-hydroxysteroid dehydrogenase. Gossypol acetate is a potent inhibitor of rat 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase, possibly inhibiting the formation of androgen in the prostate cancer cells.


Assuntos
Inibidores de 5-alfa Redutase/química , Gossipol/análogos & derivados , Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Células Intersticiais do Testículo/efeitos dos fármacos , Oxirredutases do Álcool/antagonistas & inibidores , Animais , Gossipol/farmacologia , Células Intersticiais do Testículo/enzimologia , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias da Próstata/tratamento farmacológico , Ratos Sprague-Dawley
5.
Assay Drug Dev Technol ; 17(2): 44-57, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30575417

RESUMO

Human steroid 5 alpha-reductases (S5αRs) and NADPH irreversibly reduce testosterone to the more potent dihydrotestosterone (DHT). S5αR inhibitors are useful treatments for DHT-dependent diseases, including benign prostatic hyperplasia, androgenic alopecia and hair growth, and acne. There are three S5αR isozymes, and there is a need for safer and more isozyme selective inhibitors than finasteride and dutasteride currently licensed. In this study, we review the methods used to screen for S5αR inhibitory activity and describe studies that characterize the ability of herbal preparations and their constituents to inhibit S5αRs. We identified enormous variations between studies in IC50s for finasteride and dutasteride used as standards. Accordingly, we make several recommendations: Stable isozyme specific transfection systems need creating a standardized enzyme/microsome preparation and all three isozymes, as well as androgen receptor binding, should be tested; agreed reaction conditions, especially the substrate concentrations, and separation/quantitation method optimized for high throughput screening; systematic screening of herbal compounds and most extensive use of leads to develop more potent and isozyme specific inhibitors.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/farmacologia , Produtos Biológicos/farmacologia , Descoberta de Drogas , Inibidores de 5-alfa Redutase/química , Animais , Produtos Biológicos/química , Humanos , Estrutura Molecular
6.
Bioorg Med Chem ; 26(14): 4058-4064, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30007568

RESUMO

It is known that the growth of prostate metastatic bone tumor depends on androgens, and tumor formation can start from migratory malignant cells produced in that organ. These cells exhibit grater type 1 5α-reductase (5α-R1) activity than type 2 5α-reductase. Noteworthy, both isozymes convert testosterone (T) to the more active androgen dihydrotestosterone (DHT) in the target tissues. Thus, in order to potentially improve the prognosis of this disease, in this work, seven derivatives of 17-(1H-benzimidazol-1-yl)-16-formillandrosta-5,16-dien-3ß-yl benzoate (4a-f) and 17-(1H-benzimidazol-1-yl)-3-hydroxy-16-formylandrost-5,16-diene (4) were synthesized, characterized and identified as inhibitors of type 1 5α-reductase (5αR1). These derivatives having the advantage of improved plasma half-life. The inhibitory activity of the compounds towards 5α-R1 isoenzyme was determined by conversion of T into DHT in the presence or absence of compounds 4, 4a-f. Further, in vivo experiments were also carried out, treating gonadectomized hamsters with T and/or 4, 4a-f and evaluating their effect on the diameter of hamster flank organs and on the weight of the prostatic and seminal vesicles. Results indicated that compounds 4, 4b, 4c, served as in vitro inhibitors of the enzyme 5α-R1 and pharmacological experiments showed that 4 and derivatives 4a-f decreased the diameter of the flank glands, the weight of the prostate and seminal vesicles of treated hamsters without any appreciable toxicity during observation. Noteworthy the fact that compound 4 is the product, in all cases, of the hydrolysis of the series of esters 4a-f, thus they can serve as precursors (prodrugs) of the active form 4.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Benzoatos/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/química , Animais , Benzoatos/administração & dosagem , Benzoatos/química , Cricetinae , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Conformação Molecular , Ratos , Solubilidade , Relação Estrutura-Atividade
7.
Clin Transl Sci ; 11(5): 513-522, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29877607

RESUMO

Development of an oral testosterone therapy has proven extremely challenging because of extensive and variable first-pass metabolism. We investigated the in vivo metabolism of testosterone with increasing oral doses of testosterone, both alone and with the co-administration of dutasteride (5α-reductase inhibitor) by liquid-chromatography tandem mass spectrometry (LC-MS/MS). In eugonadal men prior to dosing, the circulating concentration of testosterone, androstenedione, etiocholanolone-glucuronide, and androsterone-glucuronide was 8.6, 20.9, 9.1, and 55.3%, respectively, of the total testosterone-related species, whereas testosterone-glucuronide was ∼1%. When testosterone was dosed orally to men with experimental hypogonadism, a proportion of testosterone-glucuronide increased to 13%. Dutasteride treatment significantly decreased levels of androsterone and its metabolites. This work reveals extensive metabolism of orally dosed testosterone to androsterone glucuronide via androstenedione, with testosterone-glucuronide appearing to be the second most important metabolite. This information is of importance in the development of an effective oral testosterone therapy and may have implications for testosterone doping research.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Metaboloma , Testosterona/administração & dosagem , Testosterona/sangue , Inibidores de 5-alfa Redutase/química , Administração Oral , Área Sob a Curva , Relação Dose-Resposta a Droga , Dutasterida/administração & dosagem , Dutasterida/farmacologia , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Masculino , Testosterona/farmacocinética
8.
Mini Rev Med Chem ; 18(9): 745-775, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28971776

RESUMO

Steroid and its derivatives have been proved to have important and diverse biological functions, which present the wide spectrum of biological activities such as antitumor, antiviral, antibacterial, antimicrobial, antifungal, antioxidant, insecticidal, aromatase inhibitors, 5α-reductase inhibitors and neuromuscular blocking agents etc. Versatile features of steroid-derived compounds have emerged, so the aim of the present paper is to review the recent advances of steroid-based derivatives mainly focused on their structures and biological applications, which can be employed for further development to discover potential drug candidates.


Assuntos
Produtos Biológicos/farmacologia , Esteroides/farmacologia , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Humanos , Inseticidas/síntese química , Inseticidas/química , Inseticidas/farmacologia , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/farmacologia , Esteroides/síntese química , Esteroides/química
9.
Curr Top Med Chem ; 18(32): 2816-2834, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30659542

RESUMO

BACKGROUND: 5α-Reductase (5AR), an NADPH dependent enzyme, is expressed in most of the prostate epithelial cells. By converting testosterone (T) into more potent androgen dihydrotestosterone (DHT), it plays an important role in men physiology and represents an efficient therapeutic target for androgen-dependent diseases. Over the last few years, significant efforts have been made in order to develop 5AR inhibitors (5ARI) to treat Benign Prostatic Hyperplasia because of excessive production of DHT. METHODS: In the present study, 2D and 3D QSAR pharmacophore models have been generated for 5ARI based on known IC50 values with extensive validations. The four featured 2D pharmacophore based PLS model correlated the topological interactions (SsOHE-index); semi empirical (Quadrupole2) and physicochemical descriptors (Mol. Wt, Bromines Count, Chlorines Count) with 5AR inhibitory activity, and has the highest correlation coefficient (r2 = 0.98, q2 =0.84; F = 57.87, pred r2 = 0.88). Internal and external validation was carried out using test and proposed set of compounds. The contribution plot of electrostatic field effects and steric interactions generated by 3D-QSAR showed interesting results in terms of internal and external predictability. The well-validated 2D PLS, and 3D kNN models were used to search novel 5AR inhibitors with different chemical scaffold. The compounds were further sorted by applying ADMET properties and in vitro cytotoxicity studies against prostate cancer cell lines PC-3. Molecular docking studies have also been employed to investigate the binding interactions and to study the stability of docked conformation in detail. RESULTS: Several important hydrophobic and hydrogen bond interactions with 5AR lead to the identification of active binding sites of 4AT0 protein in the docked complex, which include the gatekeeper residues ALA 63A (Chain A: ALA63), THR 60 A (Chain A: THR60), and ARG 456 A (Chain A: ARG456), at the hinge region. CONCLUSION: Overall, this study suggests that the proposed compounds have the potential as effective inhibitors for 5AR.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Colestenona 5 alfa-Redutase/metabolismo , Simulação de Acoplamento Molecular , Hiperplasia Prostática/tratamento farmacológico , Relação Quantitativa Estrutura-Atividade , Inibidores de 5-alfa Redutase/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Estrutura Molecular , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/patologia , Software
10.
Nutrients ; 9(10)2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-28994714

RESUMO

This study aims to investigate the biological activities related to hair loss of Equisetum debile extracts, including 5α-reductase inhibition, interleukin-6 (IL-6) secretion reduction, and anti-oxidation. E. debile extracts were obtained by maceration in various solvents. Crude extract (CE) was obtained by maceration in 95% ethanol. Chlorophyll-free extract (CF) was the CE which of the chlorophyll has been removed by electrocoagulation. Hexane extract (HE), ethyl acetate extract (EA), and ethanolic extract (ET) were fraction extracts obtained from maceration in hexane, ethyl acetate, and 95% ethanol, respectively. The extracts were investigated for inhibitory activity against 5α-reductase and IL-6 secretion. Total phenolic contents (TPC) were investigated and antioxidant activities were determined by means of 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2'-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assays. The inhibition of lipid peroxidation was determined by the ferric thiocyanate method. The cytotoxicity of the extracts on dermal papilla cells and irritation test by hen's egg test chorioallantoic membrane assay were also investigated. All extracts could inhibit 5α-reductase and decrease IL-6 secretion in lipopolysaccharide-stimulated macrophage. The antioxidant activity of E. debile extracts was directly related to their TPC. ET which contained the highest TPC (68.8 ± 6.7 mg GA/g) showed the highest equivalent concentration (EC1) of 289.1 ± 26.4 mM FeSO4/g, TEAC of 156.6 ± 34.6 mM Trolox/g, and 20.0 ± 6.0% DPPH inhibition. However, EA exhibited the highest inhibition against lipid peroxidation (57.2 ± 0.4%). In addition, EA showed no cytotoxicity on dermal papilla cell line and no irritation on chorioallantoic membrane of hen's eggs. In conclusion, EA was suggested as the most attractive ingredients for functional food and nutraceuticals because of the high inhibitory activity against 5α-reductase, IL-6 secretion, and lipid peroxidation inhibition.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Alopecia/prevenção & controle , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Suplementos Nutricionais , Equisetum/química , Alimento Funcional , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/isolamento & purificação , Inibidores de 5-alfa Redutase/toxicidade , Alopecia/enzimologia , Alopecia/fisiopatologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/toxicidade , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/toxicidade , Benzotiazóis/química , Compostos de Bifenilo/química , Linhagem Celular Tumoral , Embrião de Galinha , Cloretos/química , Colestenona 5 alfa-Redutase/metabolismo , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/patologia , Compostos Férricos/química , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Fenóis/isolamento & purificação , Fenóis/farmacologia , Picratos/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Neoplasias da Próstata/enzimologia , Células RAW 264.7 , Solventes/química , Ácidos Sulfônicos/química
11.
Bioorg Med Chem Lett ; 27(17): 4212-4217, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28757062

RESUMO

Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17ß-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Amidas/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Amidas/síntese química , Amidas/química , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade
12.
Skin Pharmacol Physiol ; 30(4): 197-204, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28689207

RESUMO

BACKGROUND/AIMS: Androgenetic alopecia is an extremely common dermatological disorder affecting both men and women. Oral finasteride (FNS), a synthetic 4-aza-3-oxosteroid compound with poor aqueous solubility, blocks the peripheral conversion of testosterone to dihydrotestosterone (DHT) in a significant reduction in DHT concentration, achieving satisfactory results in alopecia treatment. However, its oral intake generally causes severe side effects. Considering that there is currently no scientifically proven treatment, new drug delivery systems able to improve alopecia therapy are urgently required. METHODS: In this study, polymeric nanoparticles have been proposed as a new carrier for topical delivery of FNS in hair follicles. RESULTS AND CONCLUSIONS: Polymeric nanoparticles, prepared by using a modified method of the emulsification/solvent diffusion, showed a mean particle size around 300 nm, which may be sufficient for reaching the dermis and hair follicles and negative zeta potential values. Scanning electron microscope measurements showed that all the polymeric nanoparticles exhibited a spherical shape and a smooth surface regardless of their composition. A high encapsulation efficiency was achieved for FNS (79.49 ± 0.47%). In vitro release assays in physiological conditions demonstrated that nanoparticles yielded a prolonged release of FNS for 3 h. Skin assays through an in vitro permeation study demonstrated that nanoparticles had low levels of penetration of FNS, improving its time residence onto the skin. All excipients used in nanoparticle composition and in 3 different vehicles were safe. These results suggest that the proposed novel formulation presents several good characteristics indicating its suitability for dermal delivery of FNS for alopecia treatment.


Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Portadores de Fármacos/administração & dosagem , Finasterida/administração & dosagem , Ácido Láctico/administração & dosagem , Nanopartículas/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Inibidores de 5-alfa Redutase/química , Adulto , Alopecia/tratamento farmacológico , Cosméticos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Finasterida/química , Humanos , Ácido Láctico/química , Nanopartículas/química , Tamanho da Partícula , Poloxâmero/administração & dosagem , Poloxâmero/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Pele/efeitos dos fármacos , Testes Cutâneos , Adulto Jovem
13.
Drug Des Devel Ther ; 11: 1681-1692, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28652706

RESUMO

Finasteride (FIN) is a Class II candidate of the Biopharmaceutics Classification System (BCS). The lipophilic cavity of cyclodextrins (CyDs) enables it to construct a non-covalent inclusion complex with different insoluble drugs. Only ß-cyclodextrin (ß-CyD) and hydroxypropyl-ß-CyD (HP-ß-CyD) have been previously examined with FIN. This study aimed to investigate the consistence of FIN with different kinds of ß-CyDs, including dimethyl-ß-cyclodextrin (DM-ß-CyD), carboxymethyl-ß-cyclodextrin (CM-ß-CyD), HP-ß-CyD, sulfobutyl ether-ß-cyclodextrin (SBE-ß-CyD), and ß-CyD, by the coprecipitation method. The resultant inclusion systems were characterized by differential scanning calorimetry, infrared spectroscopy, X-ray diffractometry, and dissolution studies. Moreover, molecular docking for the selected inclusion systems was carried out to explore the suitable arrangements of FIN in the cavity of ß-CyD or its derivatives. The results suggested that the DM-ß-CyD inclusion system gave the higher complexation efficiency for improvement in solubility of FIN and hence enhancement of its bioavailability. Pharmacokinetic parameters displayed a higher absorption rate and higher area under the curve of the FIN/DM-ß-CyD inclusion complex when compared with the drug alone, which indicates an improvement in the absorption and bioavailability of FIN in the DM-ß-CyD inclusion system.


Assuntos
Inibidores de 5-alfa Redutase/farmacocinética , Finasterida/farmacocinética , Simulação de Acoplamento Molecular , beta-Ciclodextrinas/química , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/sangue , Inibidores de 5-alfa Redutase/química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Composição de Medicamentos , Liberação Controlada de Fármacos , Finasterida/administração & dosagem , Finasterida/sangue , Finasterida/química , Meia-Vida , Absorção Intestinal , Taxa de Depuração Metabólica , Modelos Biológicos , Difração de Pó , Coelhos , Solubilidade , Espectrofotometria Infravermelho
14.
Steroids ; 124: 29-34, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28549802

RESUMO

5α-Reductase is a key enzyme responsible for dihydrotestosterone biosynthesis and has been recognized as an important target for discovering new drugs against benign prostatic hyperplasia (BPH). In this study, a series of novel steroidal androst-3,5-diene-3-carboxylic acids have been designed and synthesized. Biological evaluations were performed on their 5α-reductase inhibitory activities by both in vitro enzyme inhibition assay and in vivo by prostate weighing method. Results showed that most of them displayed excellent 5α-reductase inhibitory potency. Detailed evaluation indicated that most of the compounds displayed slightly higher inhibition potency towards type 2 isozyme. Among all the compounds, 16a was found to be the most potential inhibitor with the IC50 of 0.25µM and 0.13µM against type 1 and 2 isozymes respectively. In vivo 5a-reductase inhibitory evaluation of 16a also showed a more significant reduction effect (p<0.001) in rat prostate weight than epristeride. Furthermore, the results of in silico ADME study indicated that compound 16a exhibited good pharmacokinetic properties. Thus, 16a could serve as promising lead candidates for further study.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Desenho de Fármacos , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacocinética , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Técnicas de Química Sintética , Simulação por Computador , Masculino , Ratos
15.
Chem Pharm Bull (Tokyo) ; 65(3): 253-260, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28250347

RESUMO

Avicequinone C (5a), a furanonaphthoquinone isolated from the Thai mangrove Avicennia marina has been shown previously to have interesting steroid 5α-reductase type 1 inhibitory activity. In this study, a series of avicequinone C analogues containing furanonaphthoquinone with different degrees of saturation and substituents at the furan ring were synthesized. The resulting synthetic avicequinone C and analogues (5a-f) along with some related compounds including 2,5-dihydroxy-1,4-benzoquinone (6) and natural naphthoquinones such as lawsone (7a) and lapachol (7b) were evaluated for their in vitro cell viability and steroid 5α-reductase type 1 inhibitory activities using the cultured cell line of human keratinocytes (HaCaT). This cell-based bioassay was performed based on a direct detection of the enzymatic product dihydrotestosterone (2) by using a non-radioactive high performance thin layer chromatography (HPTLC) method. Among the furanonaphthoquinones in this series, 5e having a propionic substituent at furan ring possessed approximately 22-fold more potent than the original isolated compound 5a. However, the compounds without furan motif such as 6, 7a and b could not inhibit the activity of steroid 5α-reductase. Molecular docking results of the in silico three-dimensional steroid 5α-reductase type 1-reduced nicotinamide adenine dinucleotide phosphate (NADPH) binary complex was performed via AutoDock Vina and it illustrated that the furanonaphthoquinone moiety and the substituent at furan ring might play a key role as pharmacophores for the steroid 5α-reductase inhibitory activity.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Simulação de Acoplamento Molecular , Quinonas/farmacologia , Inibidores de 5-alfa Redutase/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade
16.
Curr Clin Pharmacol ; 12(1): 31-35, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28294070

RESUMO

BACKGROUND: Androgenetic alopecia is a common condition characterized by thinning of scalp hair. Conversion of testosterone to dihydrotestosterone, a more potent androgen, by the enzyme 5-α-reductase is responsible for underlying pathogenesis. Dutasteride, a synthetic 4-azasteroid, is a selective and competitive inhibitor of both type-1 and type-2 isoenzymes of 5-α-reductase. Finasteride and minoxidil are the only approved drugs for androgenetic alopecia. Dutasteride has been demonstrated to be effective in several randomized, double-blind, placebo controlled trials in androgenetic alopecia. In this review, after the pharmacology of dutasteride, the authors have discussed the status of dutasteride in androgenetic alopecia and have compared its efficacy with that of finasteride. OBJECTIVE: This article aims to review the current status of dutasteride in androgenetic alopecia. The structure, mechanism of action, pharmacokinetics and side effects are discussed along with its comparison with finasteride in androgenetic alopecia. METHOD: The main sources of our information were Medline Pubmed, Google scholar and Scopus including original articles and review articles. The keywords 'dutasteride', 'dutasteride in androgenetic alopecia' were used for search. CONCLUSION: Like finasteride, dutasteride is now becoming popular treatment option in AGA, due to its good response shown by various randomized control studies and meta-analysis. Also, in most of these studies, dutasteride was found to be better than finasteride with comparable adverse effects. Therefore, dutasteride could become a treatment of choice for AGA in near future.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Alopecia/tratamento farmacológico , Dutasterida/uso terapêutico , Cabelo/efeitos dos fármacos , Inibidores de 5-alfa Redutase/efeitos adversos , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacocinética , Alopecia/metabolismo , Alopecia/fisiopatologia , Animais , Di-Hidrotestosterona/metabolismo , Dutasterida/efeitos adversos , Dutasterida/química , Dutasterida/farmacocinética , Feminino , Finasterida/uso terapêutico , Cabelo/crescimento & desenvolvimento , Cabelo/metabolismo , Humanos , Masculino , Resultado do Tratamento
17.
Mini Rev Med Chem ; 17(7): 593-602, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27484626

RESUMO

BACKGROUND: Proliferation of the smooth muscle and epithelial cells within the prostatic transition zone in older men leads to benign prostatic hyperplasia (BPH), which is hallmarked by the troublesome lower urinary tract symptoms. The affair responsible for the initiation and promotion of disease is still unresolved, though alpha-blockers and 5α-reductase inhibitors are used as management options for relief from the dynamic and static components respectively. METHOD: Combination therapy including both the alpha blocker and 5α-reductase inhibitor is emerging as inclusive parcel for treatment. However, selective androgen receptor modulators (SARM) and selective estrogen receptor modulators (SERM) are the other management resources, which are in the limelight. RESULT: This review gives a glimpse of BPH and the various chemical entities which have been reported in literature till date for the condition since 2005.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Inibidores de 5-alfa Redutase/química , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Hiperplasia Prostática/patologia , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade
18.
J Asian Nat Prod Res ; 19(8): 774-779, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28030961

RESUMO

Three new xanthones (1-3), together with five known ones (4-8), were isolated from whole herb of Swertia bimaculata. Their structures were established on the basis of detailed spectroscopic analysis (1D- and 2D-NMR, HRESIMS, UV, and IR) and comparison with data reported in the literature. New isolates were evaluated for their anti-5α-reductase activity. The results revealed that all new compounds showed weak activity with reductase inhibitions of 40.5 ± 2.8, 38.6 ± 2.5, and 48.9 ± 3.0%, respectively.


Assuntos
Inibidores de 5-alfa Redutase/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Swertia/química , Xantonas/isolamento & purificação , Xantonas/farmacologia , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Medicamentos de Ervas Chinesas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Xantonas/química
19.
Steroids ; 116: 67-75, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27789379

RESUMO

Steroid 5α-reductase (S5αR) plays an important role in metabolizing testosterone into active androgen dihydrotestosterone (DHT) which is involved in many androgen dependent disorders, such as androgenic alopecia, benign prostatic hyperplasia and acne. The method for screening for S5αR inhibition is key in finding new antagonists. In this study, the label-free S5αR inhibitory assay using LC-MS was developed. S5αR type 1 enzyme was obtained from LNCaP prostate cancer cells. The enzymatic assay was optimised for enzyme-substrate (testosterone) concentration, NADPH-cofactor concentration, solvent tolerance, enzyme activity stability and incubation time. The developed assay was validated by measuring the signal to background ratio (S/B), the signal to noise ratio (S/N), the signal window (SW) and the zeta factor Z' in accordance with published bioassay guidelines. The enzymatic reaction was performed in 96-well plates and DHT formation was determined by LC-MS. S/B, S/N, SW and Z' factor were well above acceptable criteria and the reproducibility was good using Z' factor other 3days and further validated by dutasteride and finasteride inhibition. The method was successfully applied to quantify S5αR inhibitory activity of some Thai herbal extracts. Two plant extracts, Impatiens balsamina L. and Curcuma longa L. showed IC50 at 5.4±0.2 and 9.0±1.2µgmL-1 and are therefore promising sources of new S5αR inhibitors. The assay has high selectability and reproducibility and suited to medium throughput screening required by phytochemistry.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/farmacologia , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Inibidores de 5-alfa Redutase/química , Linhagem Celular Tumoral , Curcuma/química , Di-Hidrotestosterona/metabolismo , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Impatiens/química , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Reprodutibilidade dos Testes
20.
Molecules ; 21(7)2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27399661

RESUMO

Adina rubella Hance (AR), a plant native to Korea, has been used as traditional medicine for dysentery, eczema, intoxication, and external hemorrhages. Previous phytochemical studies of AR have reported several components, including terpenoids, phenolics, and alkaloids. The current study evaluated the anti-oxidative and anti-inflammatory activities and 5α-reductase inhibition of isolated compounds of AR leaves to find a potential therapeutic agent for benign prostatic hypertrophy (BPH). Repeated chromatographic isolation of an 80% acetone extract of AR leaves yielded seven phenolic compounds: caffeic acid (1), chlorogenic acid (2), methyl chlorogenate (3), quercetin-3-rutinoside (4), kaempferol-3-O-α-l-rhamnopyranosyl-(1→6)-ß-d-glucopyranoside (5), hyperoside (6), and grandifloroside (7). Compound 7 is a novel compound in AR. Caffeoyl derivatives 1-3 and 7 showed good anti-oxidative activities. In particular, caffeic acid (1) and grandifloroside (7) showed potent anti-inflammatory activities, and 7 also exhibited potent inhibitory activity against TNF-α and 5α-reductase. Our results show that the extract and grandifloroside (7) from leaves of AR might be developed as a source of potent anti-oxidative and anti-inflammatory agents and therapeutic agent for BPH.


Assuntos
Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Fenóis/química , Fenóis/farmacologia , Folhas de Planta/química , Rubiaceae/química , Inibidores de 5-alfa Redutase/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular , Citocinas/biossíntese , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Estrutura Molecular , Fenóis/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia
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