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1.
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
2.
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
3.
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
5.
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
6.
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
7.
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
8.
Curr Med Chem ; 23(8): 792-815, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26861003

RESUMO

This article summarizes the importance of different targets such as 5α-reductase, 17ß-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Androgênios/metabolismo , Di-Hidrotestosterona/farmacologia , Descoberta de Drogas , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Di-Hidrotestosterona/síntese química , Di-Hidrotestosterona/química , Humanos , Masculino , Conformação Molecular , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/enzimologia , Relação Estrutura-Atividade
9.
Bioorg Med Chem ; 24(4): 779-88, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26780831

RESUMO

In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-D-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC50 being 15.6nM as compared to clinically used drug finasteride (40nM). There was also a significant inhibition of 5AR-1 with IC50 547nM compared to finasteride (453nM).


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Androstanos/síntese química , Antineoplásicos/síntese química , Pregnanos/síntese química , Próstata/efeitos dos fármacos , Tetrazóis/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Androstanos/farmacologia , Androstenodiona/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Colestenona 5 alfa-Redutase/metabolismo , Epididimo/efeitos dos fármacos , Epididimo/enzimologia , Finasterida/farmacologia , Expressão Gênica , Células HEK293 , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Masculino , Plasmídeos/química , Plasmídeos/metabolismo , Pregnanos/farmacologia , Próstata/enzimologia , Ratos , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/enzimologia , Relação Estrutura-Atividade , Tetrazóis/farmacologia , Transfecção
10.
J Enzyme Inhib Med Chem ; 31(6): 908-14, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26394987

RESUMO

5α-R isozymes (types 1 and 2) play an important role in prostate gland development because they are responsible for intraprostatic dihydrotestosterone (DHT) levels when the physiological serum testosterone (T) concentration is low. In this study, we synthesized seven novel dehydroepiandrosterone derivatives with benzimidazol moiety at C-17, and determined their effect on the activity of 5α-reductase types 1 and 2. The derivatives with an aliphatic ester at C-3 of the dehydroepiandrosterone scaffold induced specific inhibition of 5α-R1 activity, whereas those with a cycloaliphatic ester (cyclopropyl, cyclobutyl, or cyclopentyl ring) or an alcohol group at C-3 inhibited the activity of both isozymes. Derivatives with a cyclohexyl or cycloheptyl ester at C-3 showed no inhibitory activity. In pharmacological experiments, derivatives with esters having an alcohol or the aliphatic group or one of the three smaller cycloaliphatic rings at C-3 decreased the diameter of male hamster flank organs, with the cyclobutyl and cyclopentyl esters exhibiting higher effect. With exception of the cyclobutyl and cyclopentyl esters, these compounds reduced the weight of the prostate and seminal vesicles.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Desidroepiandrosterona/farmacologia , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Animais , Colestenona 5 alfa-Redutase/isolamento & purificação , Cricetinae , Desidroepiandrosterona/síntese química , Desidroepiandrosterona/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/isolamento & purificação , Isoenzimas/metabolismo , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Ratos , Relação Estrutura-Atividade
11.
Bioorg Med Chem ; 23(24): 7535-42, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26631442

RESUMO

Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5α-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR). When this mechanism is altered, androgen-dependent diseases, including prostate cancer, could result. The aim of this study was to synthesize several 16-dehydropregnenolone acetate derivatives containing a triazole ring at C-21 and a linear or alicyclic ester moiety at C-3 of the steroidal skeleton. These steroids were designed as potential inhibitors of the activity of both types (1 and 2) of 5α-reductase. The cytotoxic activity of these compounds was also evaluated on a panel of PC-3, MCF7, and SK-LU-1 human cancer cell lines. The results from this study showed that with the exception of steroids 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3ß-yl-propionate and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3ß-yl-pentanoate, the compounds exhibit a lower inhibitory activity for both isoenzymes of 5α-reductase than finasteride. Furthermore the 3ß-hydroxy-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-20-one and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3ß-yl-acetate derivatives display 80% cytotoxic activity on the SK-LU-1 cell line. These results also indicated that the triazole derivatives, which have a hydroxyl or acetoxy group at C-3, could have an anticancer effect, whereas the derivatives with a alicyclic ester group at C-3 do not show biological activity.


Assuntos
Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Pregnenolona/análogos & derivados , Inibidores de 5-alfa Redutase/síntese química , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Humanos , Masculino , Mesocricetus , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Pregnenolona/síntese química , Pregnenolona/química , Pregnenolona/farmacologia , Ratos
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 34(12): 1830-3, 2014 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-25537913

RESUMO

OBJEVTIVE: To synthesize phenoxybutyric acid derivatives as 5α-reductase inhibitors and test their biological activities in vitro. METHODS: Eight analogues as nonsteroidal 5α-reductase inhibitors were designed and synthesized by substitution reaction of 6-(4-phenyl-piperazine-1-yl)-3(2H)-pyridazinone with phenoxybutyric acid derivatives. RESULTS AND CONCLUSION: The structures of the compounds were characterized by 1H-NMR and MS. Biological evaluation indicated that 7 out of the 8 compounds exhibited moderate 5α-reductase inhibitory activities, especially the compounds A1 and A7 with inhibition rates reaching 12.50% and 19.64% at the concentration of 3.3 × 10⁻5 mol/L, respectively.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Butiratos/farmacologia , Desenho de Fármacos , Butiratos/química
13.
Steroids ; 92: 13-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25278254

RESUMO

Taking pregnenolone as the starting material, two series of pyrazolinyl and pyrazolyl pregnenolones were synthesized through different routes. The synthesis of the analogs of both series is multistep and proceeds in good overall yields. While the key step in the synthesis of pyrazolinyl pregnenolones is the heterocyclization of benzylidine derivatives (3) in presence of hydrazine hydrate, it is the condensation of 3ß-hydroxy-21-hydroxymethylidenepregn-5-en-3ß-ol-20-one (5) with phenylhydrazine in the synthesis of pyrazolyl derivatives. Compounds of both the series were tested for their 5α-reductase inhibitory activities. Amongst all the compounds screened for their 5α-reductase inhibitory activities, compound 4b, 4c and 6b were found to be the most active.


Assuntos
Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/síntese química , Pirazóis/química , Pirazóis/síntese química , Finasterida/síntese química , Finasterida/química , Humanos , Masculino , Pregnenolona/química
14.
Curr Top Med Chem ; 13(16): 2047-61, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23895091

RESUMO

We herein report the synthesis of 3ß-substituted amides of 17a-aza-D-homo-4-androsten-17-one (11a-11r) from commercially available Diosgenin as the starting material. The structures of newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR and mass spectrometry. All the synthesized analogues were tested for their 5α- reductase inhibitory and antimicrobial activity, some of them exhibit moderate to potent activity comparable to the reference drugs. Among the synthesized derivatives the analogue (11r) 3ß-(indonlylbutanamido)-17a-aza-D-homo-4- androsten-17-one was found to be active against both 5α-reductase enzyme and microbial strains, whereas the analogue (11i) 3ß-(3,4-dimethoxy-benzamido)-17a-aza-D-homo-4-androsten-17-one was found to be the least active. The detailed 5α-reductase inhibitors and antimicrobial activities of the synthesized compounds were reported.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Amidas/química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Azasteroides/farmacologia , Colestenona 5 alfa-Redutase/antagonistas & inibidores , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Azasteroides/síntese química , Azasteroides/química , Bactérias/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
15.
Steroids ; 78(7): 693-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23499827

RESUMO

3,17-Dicarboxamido-androst-3,5,16-triene derivatives possessing various amine moieties were synthesized under mild conditions using palladium-catalyzed homogeneous aminocarbonylation as key reaction. Compounds containing the corresponding iodoalkene functionalities, i.e., 17-iodo-16-ene and 3-iodo-3,5-diene structural motifs, were used in the aminocarbonylation and the N-nucleophiles were varied systematically. Three amines, such as tert-butylamine, piperidine and methyl alaninate were used as N-nucleophiles in the aminocarbonylation. All variations of 3,17-dicarboxamides were synthesized using this methodology. Androst-4-ene-3,17-dione was used as starting material. The synthetic strategy of the multistep synthesis was based on the systematic variation and consecutive use of three different reactions: (i) the protection/deprotection of one of the keto functionalities (3-one or 17-one) as ethylene ketals, (ii) the transformation of the other keto group to iodoalkene functionality via its hydrazone, and (iii) palladium-catalyzed aminocarbonylation of the iodoalkene functionality.


Assuntos
Inibidores de 5-alfa Redutase/química , Androstanos/química , Paládio/química , Inibidores de 5-alfa Redutase/síntese química , Catálise , Estrutura Molecular
16.
J Enzyme Inhib Med Chem ; 28(6): 1247-54, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23051174

RESUMO

The aim of these studies was to synthesize twelve ester derivatives of dehydroepiandrosterone with therapeutic potential. The effect of 1-12 was demonstrated in the flank organs of gonadectomized hamsters treated with testosterone and the synthesized steroids. In vitro studies were carried out determining the IC50 values for the inhibition of the activity of 5α-reductase type 1 and 2, which are present in rat liver and human prostate respectively. The binding of 1-12 to the androgen receptors (AR) was determined using rat's prostate cytosol. Steroids 1-12 containing different substituents in the phenyl group of the ester moiety in C-3 reduced the flank organs and inhibited the activity of 5α-R type 1; however only steroids 1 and 2 inhibited 5α-R type 2. 1-12 did not bind to the AR. The modification of one atom of the substituents in the phenyl group of the ester moiety in C-3 changed their biological potency (IC50).


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Androstenos/farmacologia , Colestenona 5 alfa-Redutase/antagonistas & inibidores , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Androstenos/síntese química , Androstenos/química , Animais , Colestenona 5 alfa-Redutase/metabolismo , Relação Dose-Resposta a Droga , Humanos , Concentração de Íons de Hidrogênio , Fígado/enzimologia , Masculino , Mesocricetus , Pessoa de Meia-Idade , Estrutura Molecular , Próstata/enzimologia , Ratos , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 54: 728-39, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22776417

RESUMO

In the present study, novel steroidal 17a-substituted 3-cyano-17a-aza-D-homo-3,5-androstadien-17-ones (12-19) and 17a-substituted 17-oxo-17a-aza-D-homo-3,5-androstadien-3-oic acids (20-26) were synthesized from dehydroepiandrosterone acetate (6) along with 17-oxo-19-nor-3,5-androstadien-3-oic acid (30) through a multistep synthesis. Compounds were evaluated for their in vitro 5α-reductase inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity was also determined using rat prostate weighing method. Compounds 21-23 and 25 showed potent inhibition of 5α-reductase II enzyme with IC(50) values of 54.1 ± 9.5, 22.1 ± 2.4, 72.8 ± 2.3 and 26.5 ± 4.4 nM respectively as compared to Finasteride (30.3 nM) along with a significant (p < 0.05) reduction in rat prostate weight.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Androstenodiona/síntese química , Androstenodiona/farmacologia , Colestenona 5 alfa-Redutase/antagonistas & inibidores , Inibidores de 5-alfa Redutase/química , Androstenodiona/química , Animais , Técnicas de Química Sintética , Células HEK293 , Humanos , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Masculino , Tamanho do Órgão/efeitos dos fármacos , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Ratos , Ratos Wistar
18.
Arch Pharm (Weinheim) ; 345(2): 117-22, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21997851

RESUMO

A new series of benzo[6,7]cyclohepta[1,2-d]triazolo[4,3-a]pyrimidines 8a-l was synthesized via reaction of heterocyclic thione 4 or its methyl derivatives 10 with hydrazonoyl halides 5a-l. Also, reaction of compound 4 with a mixture of chloroacetic acid and aromatic aldehyde derivatives gave benzo[6,7]cyclohepta[1,2-d]thiazolo[3,2-a]pyrimidin-3-ones 12-14. The microanalyses and spectral data of the synthesized compounds are in full agreement with their molecular structure. All the newly synthesized products were screened against 5α-reductase and showed activities with good ED(50) for all compounds.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Compostos Heterocíclicos/síntese química , Hidrazonas/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Animais , Compostos Heterocíclicos/farmacologia , Hidrazonas/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
19.
Steroids ; 76(12): 1241-6, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21729714

RESUMO

The aim of this study was to synthesize different ester derivatives of dehydroepiandrosterone with therapeutic potential as antiandrogens. The biological effect of these steroids was demonstrated in in vivo as well as in vitro experiments. In the in vivo experiments, we measured the activity of seven steroids on the weight of the prostate and seminal vesicles of gonadectomized hamsters treated with testosterone. For the in vitro studies, we determined the IC(50) values by measuring the concentration of the steroidal derivatives that inhibits 50% of the activity of 5α-reductase present in human prostate and also its binding capacity to the androgen receptors (AR) obtained from rat's prostate cytosol. The results from these experiments indicated that compounds 7 5α,6ß-dibromo-3ß-propanoyloxyandrostan-17-one, 8 5α,6ß-dibromo-3ß-butanoyloxyandrostan-17-one and 9 5α,6ß-dibromo-3ß-(3'-oxapentanoyloxy)-androstan-17-one, significantly decreased the weight of the prostate and seminal vesicles as compared to testosterone treated animals; this reduction of the weight of these glands was comparable to that produced by Finasteride 11. On the other hand, compounds 4 3ß-acetoxyandrost-5-en-17-one, 5 3ß-hexanoyloxyandrost-5-en-17-one 6 3ß-(3'-oxapentanoyloxy)-androst-5-en-17-one, 7 and 12 dehydroepiandrosterone, (commercially available) inhibited the enzyme 5α-reductase. Compounds 4, 5, 6, 8 and 9 (IC(50) values of 5.2±1.2, 0.049±0.002, 6.4±1.1, 0.10±0.045, and 6.8±0.9 nM, respectively) exhibited the highest inhibitory activity. However, none of these compounds binds to the AR.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Antagonistas de Androgênios/síntese química , Colestenona 5 alfa-Redutase/metabolismo , Desidroepiandrosterona/análogos & derivados , Animais , Cricetinae , Humanos , Masculino , Mesocricetus , Ratos
20.
Bioorg Med Chem Lett ; 21(11): 3439-42, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21515045

RESUMO

Finasteride is a synthetic 4-azasteroid compound that acts by inhibiting type II 5α-reductase, the enzyme that converts the androgen testosterone to 5α-dihydrotestosterone. It was approved by the US FDA for the treatment of benign prostatic hyperplasia and male pattern baldness. Here the acylation product of Finasteride C-18 amide N-polimod was synthesized by employing acylation reaction with polimod amide as a pivotal intermediate. The structure of the key intermediate and target molecule was confirmed by infrared spectrum, (1)H NMR and (13)C NMR spectra and mass spectrum, and the inhibition of the steroid 5α-reductase and the rats' benign prostatic hyperplasia by the new Finasteride conjugate and Finasteride was also determined. The inhibition of the Finasteride conjugate on 5α-reductase was stronger than that of Finasteride. Prostate hyperplasia of rats was reduced by Finasteride conjugate treatment similar to the Finasteride treatment. However, the Finasteride conjugate treated animals showed better viable condition than the Finasteride treated ones, suggesting the new compound may have improved toxicity profile than Finasteride.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Finasterida , Inibidores de 5-alfa Redutase/química , Acilação , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Finasterida/síntese química , Finasterida/química , Finasterida/farmacologia , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Masculino , Hiperplasia Prostática/patologia , Ratos
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