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1.
Steroids ; 159: 108652, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360417

RESUMO

A photochemical approach to 18-nor-17ß-hydroxymethyl-17α-methylandrost-13-ene unit of the long-term metabolites of 17-methylated androgenic anabolic steroids (AAS) is reported. It is based on a visible light-promoted radical decarboxylative alkynylation of steroidal redox-active ester. The developed method was used in synthesis of the long-term metabolite of AAS oxymesterone.


Assuntos
Anabolizantes/síntese química , Androstenos/síntese química , Esteroides/síntese química , Anabolizantes/química , Anabolizantes/metabolismo , Androstenos/química , Androstenos/metabolismo , Luz , Conformação Molecular , Processos Fotoquímicos , Estereoisomerismo , Esteroides/química , Esteroides/metabolismo
2.
Eur J Med Chem ; 199: 112425, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32422522

RESUMO

Several steroids (abiraterone, prednisone, testosterone, cholesterol) and the BCL-2 inhibitor bexarotene were used as starting materials to synthesize iperazinyl-spacered rhodamine B conjugates. The conjugates were screened for their cytotoxicity in SRB assays against several human tumor cell lines and found to be active in a low µM to nM range. The conjugate derived from testosterone held an EC50 = 59 nM against MCF-7 tumor cells and acted mainly by necrosis. The prednisone conjugate, however, was less cytotoxic but acted mainly by apoptosis and held a moderate selectivity against MCF-7 tumor cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Androstenos/síntese química , Androstenos/química , Androstenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Bexaroteno/síntese química , Bexaroteno/química , Bexaroteno/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/síntese química , Colesterol/química , Colesterol/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Prednisona/síntese química , Prednisona/química , Prednisona/farmacologia , Rodaminas/síntese química , Rodaminas/química , Rodaminas/farmacologia , Relação Estrutura-Atividade , Testosterona/síntese química , Testosterona/química , Testosterona/farmacologia
3.
Nature ; 580(7805): 621-627, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32179876

RESUMO

Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules1-3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Carbono/química , Técnicas de Química Sintética , Hidrogênio/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Androstenos/síntese química , Androstenos/química , Catálise , Agonismo Inverso de Drogas , Elétrons , Flúor/química , Hidroxilação , Ácidos de Lewis/química , Manganês/química , Metilação , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Oxazolidinonas/síntese química , Oxazolidinonas/química , Oxirredução , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Tetrazóis/síntese química , Tetrazóis/química
4.
Steroids ; 153: 108534, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678134

RESUMO

Seven new oxazoline, benzoxazole and benzimidazole derivatives were synthesized from 3ß-acetoxyandrosta-5,16-dien-17-carboxylic, 3ß-acetoxyandrost-5-en-17ß-carboxylic and 3ß-acetoxypregn-5-en-21-oic acids. Docking to active site of human 17α-hydroxylase/17,20-lyase revealed that all oxazolines, as well as benzoxazoles and benzimidazoles comprising Δ16 could form stable complexes with enzyme, in which steroid moiety is positioned similarly to that of abiraterone and galeterone, and nitrogen atom coordinates heme iron, while 16,17-saturated benzoxazoles and benzimidazoles could only bind in a position where heterocycle is located nearly parallel to heme plane. Modeling of the interaction of new benzoxazole and benzimidazole derivatives with androgen receptor revealed the destabilization of helix 12, constituting activation function 2 (AF2) site, by mentioned compounds, similar to one induced by known antagonist galeterone. The synthesized compounds inhibited growth of prostate carcinoma LNCaP and PC-3 cells at 96 h incubation; the potency of 2'-(3ß-hydroxyandrosta-5,16-dien-17-yl)-4',5'-dihydro-1',3'-oxazole and 2'-(3ß-hydroxyandrosta-5,16-dien-17-yl)-benzimidazole was superior and could inspire further investigations of these compounds as potential anti-cancer agents.


Assuntos
Androstadienos/farmacologia , Androstenos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Benzoxazóis/farmacologia , Oxazóis/farmacologia , Androstadienos/síntese química , Androstadienos/química , Androstenos/síntese química , Androstenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Benzoxazóis/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Oxazóis/química , Células PC-3 , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
5.
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 , Androstanos/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 , Androstanos/síntese química , Androstanos/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
6.
Chem Pharm Bull (Tokyo) ; 66(3): 334-338, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29491266

RESUMO

3ß-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene, which has a double bond between C-9 and C-11 and a phenylsulfenyl group on the terminus of the side chain, is a potential synthetic intermediate for steroids with 9,11-unsaturation or 9,11-seco skeletons. We describe here the synthesis of the title compound from 17-ethylenedioxy-3-acetoxyandrosta-3,5-dien-11-one. The introduction of an ethylene unit to 3ß-tert-butyldimethylsiloxyandrosta-5,9(11)-dien-17-one by the action of ethyltriphenylphosphonium bromide under basic conditions resulted in an inseparable mixture of two stereoisomeric products (5 : 1). However, in the subsequent step, only the (Z)-isomer was susceptible to the Lewis acid-catalyzed ene reaction with formaldehyde, giving a stereochemically pure product with the desired configuration. Within three steps, the ene-product was derivatized to the title compound, with a total yield of 53% over seven steps. Reductive terminal anion formation by treatment with lithium di-tert-butylbiphenyl (LiDBB) and subsequent nucleophilic attack on a branched aliphatic aldehyde was demonstrated, with an eye toward the introduction of side chains, especially for steroids with oxygen functionality at C-23.


Assuntos
Aldeídos/química , Androstenos/síntese química , Ácidos Cólicos/química , Androstenos/química , Catálise , Ácidos Cólicos/síntese química , Complexos de Coordenação/química , Ácidos de Lewis/química , Lítio/química , Oxirredução , Estereoisomerismo
7.
Steroids ; 128: 58-67, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29100780

RESUMO

A series of amphiphilic derivatives of (3ß,17ß)-3-hydroxyandrost-5-ene-17-carboxylic acid (1) with the polyamine spermine and three other diamines, 1,2-diaminoethane, piperazine and cadaverine, were synthesized and their antimicrobial activity and cytotoxicity were investigated. Among the target compounds, several ones showed antimicrobial activity on Gram positive and Gram negative microorganisms. The most active compounds were 20 (Streptococcus mutans CCM 7409, 3.125 µM), 16 (Streptococcus mutans CCM 7409, 12.5 µM) and 10d (Escherichia coli CCM 3954, 12.5 µM). In addition, compounds 5d, 10d, 13 and 20 displayed cytotoxicity on CEM (12.1 ±â€¯2.1 µM, 7.6 ±â€¯1.0 µM, 19.0 ±â€¯0.4 µM and 5.9 ±â€¯0.7 µM, respectively). Two additional compounds displayed medium cytotoxicity on CEM, 5a (34.6 ±â€¯5.2 µM) and 5c (37.7 ±â€¯5.9 µM). The compound 13 and 20 displayed high toxicity also on normal fibroblasts.


Assuntos
Androstenos/farmacologia , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Poliaminas/farmacologia , Androstenos/síntese química , Androstenos/química , Antibacterianos/síntese química , Antibacterianos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Escherichia coli/patogenicidade , Testes de Sensibilidade Microbiana , Poliaminas/síntese química , Poliaminas/química
8.
J Am Chem Soc ; 139(20): 6819-6822, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28463562

RESUMO

Herein we describe concise enantioselective chemical syntheses of (-)-viridin and (-)-viridiol. Our convergent approach couples two achiral fragments of similar complexity and employs an enantioselective intramolecular Heck reaction to set the absolute stereochemical configuration of an all-carbon quaternary stereocenter. To complete the syntheses of these base- and nucleophile-sensitive natural products, we conduct carefully orchestrated site- and diastereoselective oxidations and other transformations. Our work is the first to generate these targets as single enantiomers.


Assuntos
Androstenodióis/síntese química , Androstenos/síntese química , Bacteriocinas/síntese química , Androstenodióis/química , Androstenos/química , Bacteriocinas/química , Estrutura Molecular , Estereoisomerismo
9.
Steroids ; 123: 73-83, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28450070

RESUMO

In the present study, synthesis and antineoplastic activity of phenylacetic acid and benzoic acid nitrogen mustard conjugates of various steroidal oximes are reported for the first time. The conjugation was achieved through a more stable oxime-ester linkage and the resulting newly synthesized conjugates were evaluated in vitro on various human cancer cell lines for cytotoxicity. The extent of their alkylating activity was investigated by the in vitro colorimetric 4-(p-nitrobenzyl)pyridine (NBP) assay. The 17E-steroidal oxime-benzoic acid mustard ester 3ß-acetoxy-17E-[p-(N,N-bis(2-chloroethyl)amino)]benzoyloxyimino-androst-5-ene (8) emerged as the most potent conjugate having significant cytotoxicity on most of the NCI 60-cell lines. Outstanding growth inhibition was observed on the IGROV1 ovarian cancer cell line with GI50=0.937µM. In general, the D-ring derived androstene oxime-nitrogen mustard conjugates were found to possess better antineoplastic activity over a variety of cancer cells in comparison to those derived from other rings of the steroid skeleton.


Assuntos
Androstenos/síntese química , Androstenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Mecloretamina/química , Oximas/química , Androstenos/química , Androstenos/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Macrófagos/efeitos dos fármacos , Camundongos
10.
Eur J Med Chem ; 121: 737-746, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27423983

RESUMO

In this study, we report the synthesis and anti-proliferative effect of a set of eight androst-4-ene-3-one derivatives with different arylcarbamoyl groups at C-17. The novel compounds were prepared from commercially available 3ß-hydroxy-5-pregnen-20-one and evaluated against the androgen-sensitive human prostate adenocarcinoma LNCaP cell line. The cancerous cells were exposed to 50 µM of each compound and the proliferating agent testosterone (T) or dihydrotestosterone (DHT). The most potent compounds from this assay were further tested against the androgen-insensitive PC3 cell line. We also demonstrate the activity of these compounds on rat peripheral blood mononuclear cells for comparison. Both 17ß-N-[3,5-bis(trifluoromethyl)phenylcarbamoyl]androst-4-ene-3-one (6f) and 17ß-N-(1,3-thiazol-2-ylcarbamoyl)androst-4-ene-3-one (6g) exhibited a higher growth inhibitory effect than commercially available drugs finasteride, flutamide and ketoconazole on LNCaP cells in the presence and absence of androgens. In addition, 6f and 6g demonstrated high potency on PC3 cells suggesting an androgen-independent anti-proliferative effect. Moreover, the novel compounds showed a small effect on rat mononuclear cells, an indication of low toxicity.


Assuntos
Androgênios/metabolismo , Androstenos/síntese química , Androstenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias da Próstata/patologia , Androstenos/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Ratos
11.
Domest Anim Endocrinol ; 57: 1-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27285831

RESUMO

The present study was performed to measure messenger RNA levels of steroidogenic enzymes in testes and fat tissue and determine whether they are related to fat androstenone level. Real-time polymerase chain reaction experiments were performed on 26 testes and 12 adipose tissue samples from pubertal boars using 21 genes. The absence of significant correlations between fat androstenone and the transcriptional activity of the SRD5A2 and SRD5A3 genes but the high correlation coefficient with that of the SRD5A1 gene (r = 0.62, P < 0.05) suggests that the enzyme coded by SRD5A1 is mainly responsible for the last step of androstenone synthesis. The testicular transcriptional activities of CYP17, CYP11A1, CYP19A, AKR1C-pig6, SRD5A1, LHCGR, and AR were significantly correlated. Only transcriptional levels of CYP17, CYP11A1, CYP19A, SRD5A1, and AKR1C-pig6 were correlated with the fat concentration of androstenone (0.57 < r < 0.70, P < 0.05) confirming that the amount of androstenone stored in fat is related to the production in testes of androstenone and more generally to all sex steroids. Altogether, our data are in favor of a preponderant role of AKR1C-pig6 instead of HSD17B3 for testicular synthesis of steroids. Concerning fat tissue, our data do not support a significant de novo biosynthesis of steroids in porcine adipose tissues. The presence of transcripts coding for steroid enzymes, especially those of AKR1C-pig6, suggests that steroids can be transformed. None of transcript abundance was related to androstenone accumulation (P > 0.1). Therefore, steroids synthesized elsewhere can be transformed in fat tissue but synthesis of androstenone is unlikely.


Assuntos
Tecido Adiposo/fisiologia , Androgênios/metabolismo , Androstenos/síntese química , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Esteroides/biossíntese , Suínos/crescimento & desenvolvimento , Testículo/fisiologia , Animais , Masculino , Maturidade Sexual , Distribuição Tecidual
12.
Eur J Med Chem ; 111: 126-37, 2016 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-26866967

RESUMO

A series of D-ring fused 1,2,3-thiadiazole DHEA derivatives were synthesized and investigated for their activity against the growth of various tumor cell lines using the sulforhodamine B (SRB) assay. It is amazing that for these compounds, T47D cell line was much more sensitive than other tumor cell lines. The most potent saturated N-heterocyclic derivatives showed similar antitumor effect with the positive control compound ADM (adriamycin) on T47D cells, that was 44-60 folds more potent than the lead compound DHEA. Most compounds with potent antitumor activity displayed low toxicity on normal human fibroblasts (HAF). Especially compound 25 (CH33) showed an IC50 of 0.058 µM on T47D cells and its selectivity index (SI) between HAF and T47D was 364, which was 214 folds better than ADM (SI = 1.7). The apoptosis, colony formation and transwell migration assays of 25 were performed on T47D cell line. The primary mechanism study showed that 25 caused a dose-dependent induction of apoptosis, and induced phosphorylation of EphA2 and EphB3 in T47D cells. The in vivo antitumor effect of 25 was also observed in T47D tumor-bearing mice without obvious toxicity.


Assuntos
Androstenos/síntese química , Androstenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Prolina/análogos & derivados , Androstenos/química , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Prolina/síntese química , Prolina/química , Prolina/farmacologia , Relação Estrutura-Atividade
13.
Steroids ; 102: 60-4, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26216206

RESUMO

A general methodology for the synthesis of different steroidal 17-spirolactones is described. This method uses lithium acetylide of ethyl propiolate as the three carbon synthon and the method was successfully applied for the process development of drospirenone.


Assuntos
Androstenos/química , Androstenos/síntese química , Espironolactona/química , Espironolactona/síntese química
14.
Steroids ; 98: 143-52, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25804762

RESUMO

The Claisen condensations of 3ß-acetoxypregn-5-en-20-one (1) and 3ß-acetoxypregna-5,16-diene (7) with dimethyl oxalate are known to lead to 3ß-hydroxy-21-methoxalylpregn-5-en-20-one (2) and 3ß-hydroxy-21-methoxalylpregna-5,16-dien-20-one (8), respectively. The reactions of 2 with p-substituted phenylhydrazines afford pyrazol-5-yl derivatives (5) as main, and 3-yl regioisomers (4) as minor products. The corresponding reactions of 16-ene analogue 8 afford only pyrazol-5-yl regioisomer 9. Oppenauer oxidation of the pyrazolyl compounds yields the corresponding Δ(4)-3-ketosteroids. We investigated the antiandrogenic effects of new methoxycarbonylpyrazolyl compounds through determination of their in vitro inhibition of the activities of rat testicular C17,20-lyase, Δ(5)-3ß-hydroxysteroid dehydrogenase (Δ(5)-3ß-HSD) and 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3). A Δ(5)-3ß-hydroxy compound in the D-ring-saturated androst-5-ene series bearing an unsubstituted phenyl group on the pyrazolyl heterocycle (5a) proved to be a potent inhibitor of Δ(5)-3ß-HSD. The 4-methoxyphenyl derivative (5e) and the 3-oxo counterpart (6a) of 5a also displayed substantial inhibition. The other tested compounds exerted only weak inhibitory action against the enzymes investigated. The newly synthetized compounds were evaluated in vitro by means of MTT assays for antiproliferative activity against Hela (cervical carcinoma), A431 (skin epidermoid carcinoma) and MCF7 (breast adenocarcinoma) cells. In all four groups (3ß-hydroxy- and 3-ketosteroids with saturated or unsaturated ring D), the most potent analogs contain a 4-tolyl or 4-methoxyphenyl group. Compound 5d exhibited substantial antiproliferative action against the three cell lines investigated, whereas 9d inhibited the growth of Hela cells markedly. The most noteworthy inhibition was exerted by 6a against A431 cells.


Assuntos
Androstenos , Antineoplásicos , Proliferação de Células , Androstenos/síntese química , Androstenos/química , Androstenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células MCF-7
15.
Steroids ; 82: 68-76, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24486462

RESUMO

The aminosteroid derivative RM-133 has been reported to be a promising pro-apoptotic agent showing activity on various cancer cell lines. Following the development of solid-phase synthesis that generated a series of libraries of aminosteroid derivatives, we now report the development of a convenient liquid phase chemical synthesis of RM-133, the most promising candidate, in order to obtain sufficient quantities to proceed with the first preclinical assays. A simple and convergent six-step synthesis was designed and allowed the preparation of a gram-quantity scale of RM-133. This aminosteroid derivative was also fully characterized by NMR experiments which revealed an interesting mixture of conformers. Finally, the in vivo potency of RM-133 was evaluated on a xenograft model in nude mice with HL-60 tumors, which has resulted in the blocking of tumor progression by 57%.


Assuntos
Androstenos/farmacologia , Antineoplásicos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Androstenos/síntese química , Androstenos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Nus , Conformação Molecular , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade
16.
Arch Pharm (Weinheim) ; 347(3): 193-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24343881

RESUMO

In order to study the structure-activity relationship with respect to the cytotoxicity of steroidal oximes, several 6E-hydroximino-4-ene steroids and their O-alkylated derivatives were synthesized. The oxime ethers were solidified and purified by preparing their corresponding oxalate salts. The new derivatives as well as some previously synthesized ones were evaluated for in vitro antineoplastic activity against a panel of 60 cancer cell lines at 10 µM. The oximes and oxime ethers were found to have moderate to good antiproliferative activity against various leukemia, colon, melanoma, and renal cancer cell lines.


Assuntos
Androstenos/síntese química , Androstenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Oximas/síntese química , Oximas/farmacologia , Alquilação , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 70: 649-60, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24211641

RESUMO

Novel 17-exo-oxadiazoles in the androst-5-ene series were efficiently synthesized in a two-step sequence via the corresponding O-acylamidoxime intermediates (obtained from steroidal 17-carboxylic acids and amidoximes in the presence of coupling reagent), which then underwent tetrabutylammonium fluoride-induced cyclocondensation under mild reaction conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their inhibitory effect on rat testicular C17,20-lyase and their antiproliferative action on four malignant human adherent cell lines (HeLa, MCF7, A2780 and A431). One of the oxadiazolyl derivatives proved to exert significant enzyme-inhibitory action (IC50 = 0.60 µM), while some of the isolated O-acylated amidoxime intermediates displayed high cytotoxic activities on all examined cell lines, with IC50 values in the range 0.22-3.94 µM.


Assuntos
Androstenos/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Oximas/química , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Androstenos/síntese química , Androstenos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclização , Desidratação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Células MCF-7 , Masculino , Conformação Molecular , Ratos , Ratos Wistar , Esteroide 17-alfa-Hidroxilase/metabolismo , Relação Estrutura-Atividade , Testículo/enzimologia , Testículo/metabolismo
18.
Org Biomol Chem ; 11(38): 6597-603, 2013 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-23986472

RESUMO

A facile strategy for the preparation of two isomeric drospirenones 13 and 16 possessing a 14ß-hydrogen was developed, using 3ß-hydroxyandrost-5-en-17-one as the starting material. The total synthetic route involves eight steps, giving 2% overall yield. The structures of the main compounds 11, 13, 14 and 16 were determined by single crystal XRD analysis.


Assuntos
Androstenos/síntese química , Hidrogênio/química , Androstenos/química , Modelos Moleculares , Conformação Molecular , Estereoisomerismo
19.
Mol Divers ; 17(3): 547-61, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23748368

RESUMO

The reactions of 21-hydroxyprogesterone with Lawesson's reagent in toluene or [Formula: see text] gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17[Formula: see text]-ylidene)-1,3,2-oxathiaphospholane-2-sulfide (3), 4-(3-oxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17[Formula: see text]-ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D [Formula: see text]-[Formula: see text] spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete [Formula: see text] and [Formula: see text] assignments of each isomer and provided evidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity.


Assuntos
Androstenos/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Androstenos/síntese química , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Bactérias/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicorticosterona/química , Avaliação Pré-Clínica de Medicamentos , Feminino , Fungos/efeitos dos fármacos , Células HeLa , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Testes de Sensibilidade Microbiana , Compostos Organotiofosforados/química
20.
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
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