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[PMID]: 28743598 [Au] Autor: Ebihara K; Fujiwara H; Awale S; Dibwe DF; Araki R; Yabe T; Matsumoto K [Ad] Endereço: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. [Ti] Título: Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: A novel animal model of ASD. [So] Source: Behav Brain Res;334:6-15, 2017 09 15. [Is] ISSN: 1872-7549 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABA receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD. [Mh] Termos MeSH primário: Androstanos Transtorno do Espectro Autista/metabolismo Encéfalo/metabolismo Modelos Animais de Doenças Pregnanolona/deficiência [Mh] Termos MeSH secundário: Inibidores de 5-alfa Redutase/farmacologia Animais Ansiedade/metabolismo Transtorno do Espectro Autista/tratamento farmacológico Transtorno do Espectro Autista/psicologia Encéfalo/efeitos dos fármacos Medo/fisiologia Feminino Asseio Animal/fisiologia Aprendizagem/fisiologia Masculino Memória/fisiologia Metilfenidato/farmacologia Camundongos Endogâmicos ICR Psicotrópicos/farmacologia Caracteres Sexuais Comportamento Social Comportamento Estereotipado/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (5-alpha Reductase Inhibitors); 0 (Androstanes); 0 (Psychotropic Drugs); 0 (SKF 105111); 207ZZ9QZ49 (Methylphenidate); BXO86P3XXW (Pregnanolone) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 180104 [Lr] Data última revisão: 180104 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170727 [St] Status: MEDLINE

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[PMID]: 28595942 [Au] Autor: Baji Á; Kiss T; Wölfling J; Kovács D; Igaz N; Gopisetty MK; Kiricsi M; Frank É [Ad] Endereço: Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary. [Ti] Título: Multicomponent access to androstano-arylpyrimidines under microwave conditions and evaluation of their anti-cancer activity in vitro. [So] Source: J Steroid Biochem Mol Biol;172:79-88, 2017 Sep. [Is] ISSN: 1879-1220 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Novel ring D- and A-fused pyrimidines in the androstane series were efficiently synthesized within 10-15min in polar protic solvents under microwave irradiation via two kinds of multicomponent heterocyclization reactions followed by spontaneous or promoted oxidation. The rates of the one-pot catalyst-free transformations of steroidal ß-ketoaldehydes, ammonium acetate and substituted benzaldehydes in EtOH were found to be affected slightly by the steric and electronic feature of the substituents on the aromatic ring of the arylaldehyde component and the different reactivities of rings D and A of the sterane core. At the same time, the acid-catalyzed Biginelli-type reaction of dihydrotestosterone acetate, urea and arylaldehydes, and subsequent Jones oxidation of the primarily formed dihydropyrimidinones led to the corresponding ring A-fused 1H-pyrimidin-2-ones in moderate yields independently of the substituents on the aromatic moiety. The synthesized compounds were tested in vitro on human cancer cell lines as well as on non-cancerous fibroblast cells by the MTT assay in order to investigate their biological effects. As a result of the pharmacological screen, a remarkable structure-function relationship has been observed as the acetylated Biginelli products exhibited higher toxicity compared to the deacetylated version of each compound. Furthermore, in case of three 2'-arylpyrimidine derivatives a strong prostate cancer cell specific activity has been identified. [Mh] Termos MeSH primário: Androstanos/síntese química Antineoplásicos/síntese química Células Epiteliais/efeitos dos fármacos Pirimidinas/síntese química [Mh] Termos MeSH secundário: Acetatos/química Aldeídos/química Androstanos/farmacologia Antineoplásicos/farmacologia Catálise Linhagem Celular Tumoral Ciclização Células Epiteliais/patologia Feminino Seres Humanos Concentração Inibidora 50 Masculino Micro-Ondas Oxirredução Pirimidinas/farmacologia Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Acetates); 0 (Aldehydes); 0 (Androstanes); 0 (Antineoplastic Agents); 0 (Pyrimidines); RRE756S6Q2 (ammonium acetate) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170822 [Lr] Data última revisão: 170822 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170610 [St] Status: MEDLINE

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[PMID]: 28396197 [Au] Autor: Amaral C; Varela CL; Maurício J; Sobral AF; Costa SC; Roleira FMF; Tavares-da-Silva EJ; Correia-da-Silva G; Teixeira N [Ad] Endereço: UCIBIO-REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. [Ti] Título: Anti-tumor efficacy of new 7α-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells. [So] Source: J Steroid Biochem Mol Biol;171:218-228, 2017 Jul. [Is] ISSN: 1879-1220 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The majority of breast cancer cases are estrogen receptor positive (ER ). Although, third-generation aromatase inhibitors (AIs) are used as first-line treatment in post-menopausal women, they cause endocrine resistance and bone loss, which limits their success. Therefore, there is a demand to discover new potent molecules, with less toxicity that can circumvent these drawbacks. Our group has previously demonstrated that new 7α-substituted steroidal molecules, 7α-(2ξ,3ξ-epoxypropyl)androsta-1,4-diene-3,17-dione (3), 7α-allylandrost-4-ene-3,17-dione (6), 7α-allylandrost-4-en-17-one (9), 7α-allyl-3-oxoandrosta-1,4-dien-17ß-ol (10) and 7α-allylandrosta-1,4-diene-3,17-dione (12) are potent AIs in placental microsomes. In this work, it was investigated their anti-aromatase activity and in vitro effects in sensitive and resistant breast cancer cells. All the steroids efficiently inhibit aromatase in breast cancer cells, allowing to establish new structure-activity relationships for this class of compounds. Moreover, the new AIs can inhibit breast cancer cell growth, by causing cell cycle arrest and apoptosis. The effects of AIs 3 and 12 on sensitive cells were dependent on aromatase inhibition and androgen receptor (AR), while for AI 9 and AI 10 were AR- and ER-dependent, respectively. In addition, it was shown that all the AIs can sensitize resistant cancer cells being their behavior similar to the sensitive cells. In summary, this study contributes to the understanding of the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs. In addition, allowed the discovery of new potent 7α-substituted androstane molecules to inhibit tumor growth and prevent endocrine resistance. [Mh] Termos MeSH primário: Androstanos/farmacologia Antineoplásicos Hormonais/farmacologia Apoptose/efeitos dos fármacos Inibidores da Aromatase/farmacologia Neoplasias da Mama/tratamento farmacológico Resistência a Medicamentos Antineoplásicos [Mh] Termos MeSH secundário: Androstanos/efeitos adversos Androstanos/química Antineoplásicos Hormonais/efeitos adversos Antineoplásicos Hormonais/química Aromatase/química Aromatase/genética Aromatase/metabolismo Inibidores da Aromatase/efeitos adversos Inibidores da Aromatase/química Neoplasias da Mama/metabolismo Neoplasias da Mama/patologia Ciclo Celular/efeitos dos fármacos Linhagem Celular Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Feminino Seres Humanos Concentração Inibidora 50 Células MCF-7 Proteínas de Neoplasias/química Proteínas de Neoplasias/genética Proteínas de Neoplasias/metabolismo Receptores Androgênicos/metabolismo Receptores Estrogênicos/metabolismo Proteínas Recombinantes/química Proteínas Recombinantes/metabolismo Relação Estrutura-Atividade [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (AR protein, human); 0 (Androstanes); 0 (Antineoplastic Agents, Hormonal); 0 (Aromatase Inhibitors); 0 (Neoplasm Proteins); 0 (Receptors, Androgen); 0 (Receptors, Estrogen); 0 (Recombinant Proteins); EC 1.14.14.1 (Aromatase); EC 1.14.14.1 (CYP19A1 protein, human) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170718 [Lr] Data última revisão: 170718 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170412 [St] Status: MEDLINE

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[PMID]: 28254377 [Au] Autor: Cortés-Benítez F; Roy J; Maltais R; Poirier D [Ad] Endereço: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec, Québec, Canada; Department of Pharmacy, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico. [Ti] Título: Impact of androstane A- and D-ring inversion on 17ß-hydroxysteroid dehydrogenase type 3 inhibitory activity, androgenic effect and metabolic stability. [So] Source: Bioorg Med Chem;25(7):2065-2073, 2017 Apr 01. [Is] ISSN: 1464-3391 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: 17ß-Hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is a major player in human endocrinology, being one of the most important enzymes involved in testosterone production. To capitalize on the discovery of RM-532-105, a steroidal 17ß-HSD3 inhibitor, we explored the effect of its backbone configuration on inhibitory activity, androgenic profile, and metabolic stability. Two modifications that greatly alter the natural shape of steroids, i.e. inversion of the methyl on carbon 13 (13α-CH instead of 13ß-CH ) and inversion of the hydrogen on carbon 5 (5ß-H instead of 5α-H), were tested after the syntheses in 6 steps of 2 isomeric forms (5α/13α-RM-532-105 (6a) and 5ß/13ß-RM-532-105 (6b), respectively) of the 17ß-HSD3 inhibitor RM-532-105 (5α/13ß-configurations). For compound 6b, a cis/trans junction of the A/B rings did not significantly alter the inhibitory activity on 17ß-HSD3 (IC =0.15µM) as well as the liver microsomal stability (16.6% of 6b remaining after 1h incubation) compared to RM-532-105 (IC =0.11µM and 14.1% remaining). In contrast, a trans/cis junction of C/D rings reduced the inhibitory activity on 17ß-HSD3 (IC =1.09µM) but increased the metabolic stability with 29.4% of compound 6a remaining after incubation. The structural modifications represented by compounds 6a and 6b did not change the non-androgenicity profile of an androsterone derivative such as RM-532-105, but slightly increased its cytotoxic activity. [Mh] Termos MeSH primário: 17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores Androstanos/química Inibidores Enzimáticos/farmacologia [Mh] Termos MeSH secundário: Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 Inibidores Enzimáticos/química Seres Humanos Masculino Estrutura Molecular Neoplasias da Próstata/enzimologia Espectroscopia de Prótons por Ressonância Magnética Espectrofotometria Infravermelho [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Androstanes); 0 (Enzyme Inhibitors); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.- (17beta-hydroxysteroid dehydrogenase type 3) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170304 [St] Status: MEDLINE

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[PMID]: 28237792 [Au] Autor: Li J; Huo H; Guo R; Liu B; Li L; Dan W; Xiao X; Zhang J; Shi B [Ad] Endereço: Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China. [Ti] Título: Facile and efficient access to Androsten-17-(1',3',4')-pyrazoles and Androst-17ß-(1',3',4')-pyrazoles via Vilsmeier reagents, and their antiproliferative activity evaluation in vitro. [So] Source: Eur J Med Chem;130:1-14, 2017 Apr 21. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: In this work, twenty-seven novel steroidal pyrazole derivatives were designed and effectively synthesized with two different commercially available staring material, Isopregnanolone 1 and 5,16-Pregnadienolone 7, via the key intermediates, 17ß-(4'-formyl)pyrazolylandrost-3ß-yl formate and 17-(4'-formyl)pyrazolylandrost- 5,16-dienes-3ß-yl formate, which were obtained from the cyclization of steroidal phenylhydrazone with Vilsmeier reagent catalyzed by phosphorous oxychloride followed by hydrolysis, then Borch reduction to afford the target derivatives under mild conditions. Structures of these compounds were identified by H NMR, C NMR and high resolution mass spectrometry. Based on our previous work, the cytotoxicity of these derivatives were evaluated by the SRB method against 293T cell lines and three cancer cell lines: A549, Hela and MCF-7. The results indicated that compounds 5b-d, and 11a-e exhibited moderate to high cytotoxic activities with IC values ranging from 0.62 to 7.51 µM. Among the eight hybrids, compound 11b, with an ethyl amino and a dien-pregn moieties showed the highest potency, with an IC values of 0.87 µM and 0.53 µM for 293T cell lines and Hela cell lines, respectively. Some structure-activity relationships among the groups of the twenty-seven derivatives are discussed and identify several determinants important for the activity of these compounds. What's more, further molecular mechanism studies suggested that 11b one of the most potent derivatives caused Hela cell lines apoptosis and arrested the cell cycle at S phase in a concentration dependent manner. [Mh] Termos MeSH primário: Androstanos/química Pirazóis/química [Mh] Termos MeSH secundário: Androstanos/farmacologia Antineoplásicos/síntese química Antineoplásicos/farmacologia Apoptose/efeitos dos fármacos Pontos de Checagem do Ciclo Celular/efeitos dos fármacos Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Ensaios de Seleção de Medicamentos Antitumorais Seres Humanos Pirazóis/farmacologia Esteroides/química Esteroides/farmacologia Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Androstanes); 0 (Antineoplastic Agents); 0 (Pyrazoles); 0 (Steroids) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170322 [Lr] Data última revisão: 170322 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170227 [St] Status: MEDLINE

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[PMID]: 28182747 [Au] Autor: Kenmogne LC; Roy J; Maltais R; Rouleau M; Neveu B; Pouliot F; Poirier D [Ad] Endereço: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), Québec, Québec, Canada. [Ti] Título: Investigation of the In Vitro and In Vivo efficiency of RM-532-105, a 17ß-hydroxysteroid dehydrogenase type 3 inhibitor, in LAPC-4 prostate cancer cell and tumor models. [So] Source: PLoS One;12(2):e0171871, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: In the fight against androgen-sensitive prostate cancer, the enzyme 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is an attractive therapeutic target considering its key role in the formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an inhibitor of 17ß-HSD3, in the prostate cancer model of androgen-sensitive LAPC-4 cells xenografted in nude mice. RM-532-105 did not inhibit the tumor growth induced by 4-androstene-3,17-dione (4-dione); rather, the levels of the androgens testosterone (T) and dihydrotestosterone (DHT) increased within the tumors. In plasma, however, DHT levels increased but T levels did not. In troubleshooting experiments, the non-androgenic potential of RM-532-105 was confirmed by two different assays (LAPC-4 proliferation and androgen receptor transcriptional activity assays). The enzyme 5α-reductase was also revealed to be the predominant enzyme metabolizing 4-dione in LAPC-4 cells, yielding 5α-androstane-3,17-dione and not T. Other 17ß-HSDs than 17ß-HSD3 seem responsible in the androgen synthesis. From experiments with LAPC-4 cells, we fortuitously came across the interesting finding that 17ß-HSD3 inhibitor RM-532-105 is concentrated inside tumors. [Mh] Termos MeSH primário: 17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores Androstanos/uso terapêutico Inibidores Enzimáticos/uso terapêutico Neoplasias da Próstata/tratamento farmacológico Sulfonamidas/uso terapêutico [Mh] Termos MeSH secundário: Androstanos/farmacologia Animais Antineoplásicos/farmacologia Antineoplásicos/uso terapêutico Linhagem Celular Tumoral Proliferação Celular/efeitos dos fármacos Di-Hidrotestosterona/sangue Inibidores Enzimáticos/farmacologia Seres Humanos Masculino Camundongos Camundongos Nus Sulfonamidas/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Androstanes); 0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (RM-532-105); 0 (Sulfonamides); 08J2K08A3Y (Dihydrotestosterone); EC 1.1.- (17-Hydroxysteroid Dehydrogenases) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170828 [Lr] Data última revisão: 170828 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170210 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0171871

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[PMID]: 28029060 [Au] Autor: Liu LF; Zhang H; Qi H; Wang XM; Wang JD; Tan GS [Ad] Endereço: a School of Pharmaceutical Sciences , Central South University , Changsha , China. [Ti] Título: A new androstanoid metabolite from a soil fungus Curvularia borreriae strain HS-FG-237. [So] Source: Nat Prod Res;31(9):1080-1084, 2017 May. [Is] ISSN: 1478-6427 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: A new androstanoid metabolite, 4α-methyl-9α-methoxyandrosta-8,15-diene-3,17-dione (1), was isolated from a soil fungus Curvularia borreriae (Pleosporaceae) strain HS-FG-237. Its structure was determined by extensive spectroscopic and X-ray diffraction analyses. Compound 1 exhibited poor cytotoxicity toward HCT-116 cells by CCK-8 assay and weak anti-inflammatory activity in an ANA-1 murine macrophages model. [Mh] Termos MeSH primário: Androstanos/isolamento & purificação Ascomicetos/metabolismo Microbiologia do Solo [Mh] Termos MeSH secundário: Androstanos/química Androstanos/farmacologia Animais Anti-Inflamatórios/farmacologia Antineoplásicos/farmacologia Fermentação Células HCT116 Seres Humanos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Androstanes); 0 (Anti-Inflammatory Agents); 0 (Antineoplastic Agents) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161229 [St] Status: MEDLINE [do] DOI: 10.1080/14786419.2016.1272115

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[PMID]: 27864019 [Au] Autor: Sukhodolskaya G; Fokina V; Shutov A; Nikolayeva V; Savinova T; Grishin Y; Kazantsev A; Lukashev N; Donova M [Ad] Endereço: G.K. Skryabin Institute of Biochemistry & Physiology of Microorganisms, Russian Academy of Sciences, Prospekt Nauki, 5, Puschino, Moscow Region 142290, Russian Federation. Electronic address: sukhodolskaya@rambler.ru. [Ti] Título: Bioconversion of 6-(N-methyl-N-phenyl)aminomethyl androstane steroids by Nocardioides simplex. [So] Source: Steroids;118:9-16, 2017 Feb. [Is] ISSN: 1878-5867 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The newly synthesized (α/ß)-diastereomers of 6-(N-methyl-N-phenyl)aminomethylandrost-4-ene-3,17-dione (5) and 6-(N-methyl-N-phenyl)aminomethylandrost-4-en-17ß-ol-3-one (6) were firstly investigated as substrates for the whole cells of Nocardioides simplex VKM Ac-2033D in comparison with their unsubstituted analogs, - androst-4-ene-3,17-dione (1) and androst-4-en-17ß-ol-3-one (2). 1(2)-Dehydroderivatives were identified as the major bioconversion products from all the substrates tested. When using the mixtures of (α/ß)-stereoisomers of 5 and 6 as the substrates, only ß-stereoisomers of the corresponding 1,4-diene-steroids were formed. Along with 1(2)-dehydrogenation, N. simplex VKM Ac-2033D promoted oxidation of the hydroxyl group at C-17 position of 6: both 6(α) and 6(ß) were transformed to the corresponding 17-keto derivatives. No steroid core destruction was observed during the conversion of the 6-substituted androstanes 5 and 6, while it was significant when 1 or 2 was used as the substrate. The results suggested high potentials of N. simplex VKM Ac-2033D for the generation of novel 1(2)-dehydroanalogs. [Mh] Termos MeSH primário: Androstanos/química Androstanos/metabolismo Esteroides/química Esteroides/metabolismo [Mh] Termos MeSH secundário: Actinobacteria/metabolismo Espectroscopia de Ressonância Magnética Estrutura Molecular Estereoisomerismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Androstanes); 0 (Steroids); KT649U81FE (androstane) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170830 [Lr] Data última revisão: 170830 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161120 [St] Status: MEDLINE

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[PMID]: 27694053 [Au] Autor: Ignjatovic NL; Penov-Gasi KM; Wu VM; Ajdukovic JJ; Kojic VV; Vasiljevic-Radovic D; Kuzmanovic M; Uskokovic V; Uskokovic DP [Ad] Endereço: Institute of Technical Sciences of the Serbian Academy of Science and Arts, Knez Mihailova 35/IV, P.O. Box 377, 11000 Belgrade, Serbia. [Ti] Título: Selective anticancer activity of hydroxyapatite/chitosan-poly(d,l)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor. [So] Source: Colloids Surf B Biointerfaces;148:629-639, 2016 Dec 01. [Is] ISSN: 1873-4367 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: In an earlier study we demonstrated that hydroxyapatite nanoparticles coated with chitosan-poly(d,l)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous injection into mice. In this study we utilize an emulsification process and freeze drying to load the composite HAp/Ch-PLGA particles with 17ß-hydroxy-17α-picolyl-androst-5-en-3ß-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. H NMR and C NMR techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The thermogravimetric and differential thermal analyses coupled with mass spectrometry were used to assess the thermal degradation products and properties of A-loaded HAp/Ch-PLGA. The loading efficiency, as indicated by the comparison of enthalpies of phase transitions in pure A and A-loaded HAp/Ch-PLGA, equaled 7.47wt.%. The release of A from HAp/Ch-PLGA was sustained, neither exhibiting a burst release nor plateauing after three weeks. Atomic force microscopy and particle size distribution analyses were used to confirm that the particles were spherical with a uniform size distribution of d =168nm. In vitro cytotoxicity testing of A-loaded HAp/Ch-PLGA using MTT and trypan blue dye exclusion assays demonstrated that the particles were cytotoxic to the A549 human lung carcinoma cell line (46±2%), while simultaneously preserving high viability (83±3%) of regular MRC5 human lung fibroblasts and causing no harm to primary mouse lung fibroblasts. In conclusion, composite A-loaded HAp/Ch-PLGA particles could be seen as promising drug delivery platforms for selective cancer therapies, targeting malignant cells for destruction, while having a significantly lesser cytotoxic effect on the healthy cells. [Mh] Termos MeSH primário: Androstanos/química Antineoplásicos/química Quitosana/química Durapatita/química Ácido Láctico/química Ácido Poliglicólico/química [Mh] Termos MeSH secundário: Células A549 Androstanos/farmacocinética Androstanos/farmacologia Animais Antineoplásicos/farmacocinética Antineoplásicos/farmacologia Linhagem Celular Sobrevivência Celular/efeitos dos fármacos Células Cultivadas Liberação Controlada de Fármacos Fibroblastos/citologia Fibroblastos/efeitos dos fármacos Fibroblastos/metabolismo Seres Humanos Neoplasias Pulmonares/metabolismo Neoplasias Pulmonares/patologia Espectroscopia de Ressonância Magnética Espectrometria de Massas Camundongos Endogâmicos C57BL Microscopia de Força Atômica Microscopia Confocal Nanopartículas/química Tamanho da Partícula Espectroscopia de Infravermelho com Transformada de Fourier Termogravimetria [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Androstanes); 0 (Antineoplastic Agents); 0 (polylactic acid-polyglycolic acid copolymer); 26009-03-0 (Polyglycolic Acid); 33X04XA5AT (Lactic Acid); 9012-76-4 (Chitosan); 91D9GV0Z28 (Durapatite); KT649U81FE (androstane) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170910 [Lr] Data última revisão: 170910 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161004 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 27503457 [Au] Autor: Kovacevic SZ; Podunavac-Kuzmanovic SO; Jevric LR; Vukic VR; Savic MP; Djurendic EA [Ad] Endereço: University of Novi Sad, Faculty of Technology Novi Sad, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia. Electronic address: strahko@uns.ac.rs. [Ti] Título: Preselection of A- and B- modified d-homo lactone and d-seco androstane derivatives as potent compounds with antiproliferative activity against breast and prostate cancer cells - QSAR approach and molecular docking analysis. [So] Source: Eur J Pharm Sci;93:107-13, 2016 Oct 10. [Is] ISSN: 1879-0720 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: The problem with trial-and-error approach in organic synthesis of targeted anticancer compounds can be successfully avoided by computational modeling of molecules, docking studies and chemometric tools. It has been proven that A- and B- modified d-homo lactone and d-seco androstane derivatives are compounds with significant antiproliferative activity against estrogen-independent breast adenocarcinoma (ER-, MDA-MB-231) and androgen-independent prostate cancer cells (AR-, PC-3). This paper presents the quantitative structure-activity relationship (QSAR) models based on artificial neural networks (ANNs) which are able to predict whether d-homo lactone and/or d-seco androstane-based compounds will express antiproliferative activity against breast cancer cells (MDA-MB-231) or not. Also, the present paper describes the molecular docking study of 3ß-acetoxy-5α,6α-epoxy- (3) and 6α,7α-epoxy-1,4-dien-3-one (24) d-homo lactone androstane derivatives, as well as 4-en-3-one (15) d-seco androstane derivative, which are compounds with strong or moderate antiproliferative activity against prostate cancer cells (PC-3), and compares them with commercially available medicament for prostate cancer - abiraterone. The obtained promising results can be used as guidelines in further syntheses of novel d-homo lactone and d-seco androstane derivatives with antiproliferative activity against breast and prostate cancer cells. [Mh] Termos MeSH primário: Androstanos/farmacologia Neoplasias da Mama/patologia Proliferação Celular/efeitos dos fármacos Lactonas/farmacologia Neoplasias da Próstata/patologia [Mh] Termos MeSH secundário: Feminino Seres Humanos Masculino Simulação de Acoplamento Molecular Relação Quantitativa Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Androstanes); 0 (Lactones) [Em] Mês de entrada: 1704 [Cu] Atualização por classe: 170418 [Lr] Data última revisão: 170418 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160810 [St] Status: MEDLINE

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