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[PMID]:29353726
[Au] Autor:Czarnecka K; Chufarova N; Halczuk K; Maciejewska K; Girek M; Skibinski R; Jonczyk J; Bajda M; Kabzinski J; Majsterek I; Szymanski P
[Ad] Endereço:Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland. Electronic address: kamila.czarnecka@umed.lodz.pl.
[Ti] Título:Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment.
[So] Source:Eur J Med Chem;145:760-769, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of 9-amino-1,2,3,4-tetrahydroacridine and 5,6-dichloronicotinic acid moiety were conjugated with different linkers. Afterwards new derivatives were evaluated as potential multifunctional acetylcholinesterase inhibitors (AChEIs), anti-Alzheimer's disease (AD) drug candidates. All the compounds were synthesized and tested for capacity for the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Specifically, the most promising derivative 3b (IC = 1.02 nM) had higher inhibitory potency compared to the reference drug, tacrine. Consequently, kinetic studies of 3b compound showed a mixed-type inhibition of both AChE and BuChE. Afterwards the best potent AChE inhibitor has been examined on amyloid ß (Aß) self-induced aggregation. Furthermore, 3b compound was tested in various concentrations and had moderate activity against Aß aggregation. Inhibition of Aß aggregation was 46.63% and 19.41% at 50 µM and 5  µM concentrations, respectively. Moreover, no cytotoxicity was observed for the mentioned concentrations. Therefore, 3b compound is a promising multipotent agent for the treatment of AD.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Acridinas/farmacologia
Doença de Alzheimer/tratamento farmacológico
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/farmacologia
Ácidos Nicotínicos/farmacologia
[Mh] Termos MeSH secundário: Acridinas/química
Doença de Alzheimer/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Animais
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Relação Dose-Resposta a Droga
Electrophorus
Cavalos
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Ácidos Nicotínicos/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5,6-dichloronicotinic acid); 0 (Acridines); 0 (Amyloid beta-Peptides); 0 (Cholinesterase Inhibitors); 0 (Nicotinic Acids); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


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[PMID]:29262351
[Au] Autor:Cao W; Kayama H; Chen ML; Delmas A; Sun A; Kim SY; Rangarajan ES; McKevitt K; Beck AP; Jackson CB; Crynen G; Oikonomopoulos A; Lacey PN; Martinez GJ; Izard T; Lorenz RG; Rodriguez-Palacios A; Cominelli F; Abreu MT; Hommes DW; Koralov SB; Takeda K; Sundrud MS
[Ad] Endereço:Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USA.
[Ti] Título:The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids.
[So] Source:Immunity;47(6):1182-1196.e10, 2017 Dec 19.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CD4 T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4 T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1 hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1 mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.
[Mh] Termos MeSH primário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/imunologia
Ácidos e Sais Biliares/imunologia
Linfócitos T CD4-Positivos/imunologia
Doença de Crohn/imunologia
Ileíte/imunologia
Mucosa Intestinal/imunologia
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética
Acridinas/farmacologia
Adulto
Animais
Ácidos e Sais Biliares/metabolismo
Ácidos e Sais Biliares/farmacologia
Transporte Biológico
Linfócitos T CD4-Positivos/efeitos dos fármacos
Linfócitos T CD4-Positivos/patologia
Doença de Crohn/genética
Doença de Crohn/patologia
Modelos Animais de Doenças
Feminino
Regulação da Expressão Gênica
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/imunologia
Homeostase/imunologia
Seres Humanos
Ileíte/genética
Ileíte/patologia
Íleo/imunologia
Íleo/patologia
Imunidade nas Mucosas
Mucosa Intestinal/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Meia-Idade
Estresse Oxidativo
Transdução de Sinais
Tetra-Hidroisoquinolinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Acridines); 0 (Bile Acids and Salts); 0 (Homeodomain Proteins); 0 (Tetrahydroisoquinolines); 128559-51-3 (RAG-1 protein); N488540F94 (Elacridar)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE


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[PMID]:28468887
[Au] Autor:Gilbert-Girard S; Gravel A; Artusi S; Richter SN; Wallaschek N; Kaufer BB; Flamand L
[Ad] Endereço:Division of Infectious and Immune Diseases, CHU de Québec Research Center, Quebec City, Quebec, Canada.
[Ti] Título:Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration.
[So] Source:J Virol;91(14), 2017 Jul 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes using a mechanism that remains poorly understood. To achieve a better understanding of the HHV-6A/B integration mechanism, we made use of BRACO-19, a compound that stabilizes G-quadruplex secondary structures and prevents telomere elongation by the telomerase complex. First, we analyzed the folding of telomeric sequences into G-quadruplex structures and their binding to BRACO-19 using G-quadruplex-specific antibodies and surface plasmon resonance. Circular dichroism studies indicate that BRACO-19 modifies the conformation and greatly stabilizes the G-quadruplexes formed in G-rich telomeric DNA. Subsequently we assessed the effects of BRACO-19 on the HHV-6A initial phase of infection. Our results indicate that BRACO-19 does not affect entry of HHV-6A DNA into cells. We next investigated if stabilization of G-quadruplexes by BRACO-19 affected HHV-6A's ability to integrate its genome into host chromosomes. Incubation of telomerase-expressing cells with BRACO-19, such as HeLa and MCF-7, caused a significant reduction in the HHV-6A integration frequency ( < 0.002); in contrast, BRACO-19 had no effect on HHV-6 integration frequency in U2OS cells that lack telomerase activity and elongate their telomeres through alternative lengthening mechanisms. Our data suggest that the fluidity of telomeres is important for efficient chromosomal integration of HHV-6A and that interference with telomerase activity negatively affects the generation of cellular clones containing integrated HHV-6A. HHV-6A/B can integrate their genomes into the telomeres of infected cells. Telomeres consist of repeated hexanucleotides (TTAGGG) of various lengths (up to several kilobases) and end with a single-stranded 3' extension. To avoid recognition and induce a DNA damage response, the single-stranded overhang folds back on itself and forms a telomeric loop (T-loop) or adopts a tertiary structure, referred to as a G-quadruplex. In the current study, we have examined the effects of a G-quadruplex binding and stabilizing agent, BRACO-19, on HHV-6A chromosomal integration. By stabilizing G-quadruplex structures, BRACO-19 affects the ability of the telomerase complex to elongate telomeres. Our results indicate that BRACO-19 reduces the number of clones harboring integrated HHV-6A. This study is the first of its kind and suggests that telomerase activity is essential to restore a functional telomere of adequate length following HHV-6A integration.
[Mh] Termos MeSH primário: Quadruplex G
Herpesvirus Humano 6/fisiologia
Conformação de Ácido Nucleico
Telômero/química
Telômero/metabolismo
Integração Viral
[Mh] Termos MeSH secundário: Acridinas/metabolismo
Linhagem Celular
Dicroísmo Circular
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acridines); Z7C5CD91WI (BRACO-19)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


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[PMID]:28882502
[Au] Autor:Torikai K; Koga R; Liu X; Umehara K; Kitano T; Watanabe K; Oishi T; Noguchi H; Shimohigashi Y
[Ad] Endereço:Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. Electronic address: torikai@chem.kyushu-univ.jp.
[Ti] Título:Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents.
[So] Source:Bioorg Med Chem;25(20):5216-5237, 2017 Oct 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERß (IC < µM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
[Mh] Termos MeSH primário: Acridinas/farmacologia
Antineoplásicos/farmacologia
Desenho de Drogas
Antagonistas de Estrogênios/farmacologia
Estrogênios/metabolismo
[Mh] Termos MeSH secundário: Acridinas/síntese química
Acridinas/química
Antineoplásicos/síntese química
Antineoplásicos/química
Ligação Competitiva/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Antagonistas de Estrogênios/síntese química
Antagonistas de Estrogênios/química
Células HeLa
Seres Humanos
Células MCF-7
Estrutura Molecular
Receptores Estrogênicos/antagonistas & inibidores
Receptores Estrogênicos/metabolismo
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acridines); 0 (Antineoplastic Agents); 0 (Estrogen Antagonists); 0 (Estrogens); 0 (Receptors, Estrogen)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE


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[PMID]:28763648
[Au] Autor:Yuan Z; Chen S; Chen C; Chen J; Chen C; Dai Q; Gao C; Jiang Y
[Ad] Endereço:Department of Chemistry, Tsinghua University, Beijing, 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China.
[Ti] Título:Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy.
[So] Source:Eur J Med Chem;138:1135-1146, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:PARP-1 could repair the DNA damages induced by Topo inhibitors, therefore inhibiting Topo and PARP-1 simultaneously might be able to overcome resistance and improve outcomes. In this study a series of 4-amidobenzimidazole acridines were designed and synthesized as dual Topo and PARP-1 inhibitors. Compound 11l displayed good inhibitory activities against Topo and PARP-1, as well as significantly inhibited cancer cells proliferation. Further mechanistic evaluations indicated that 11l treatment in MCF-7 cells induced accumulated DNA double-strand breaks, prompted remarkable apoptosis, and caused prominent G0/G1 cell cycle arrest. Moreover, 11l greatly suppressed tumor growth in mice, and displayed favorable metabolic properties in liver microsomes. Our study suggested that single agents inhibiting Topo and PARP concurrently might be an alternative for cancer therapy and 11l represented a potential lead compound for development of antitumor agents.
[Mh] Termos MeSH primário: Acridinas/farmacologia
Antineoplásicos/farmacologia
DNA Topoisomerases/metabolismo
Desenho de Drogas
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Inibidores da Topoisomerase/farmacologia
[Mh] Termos MeSH secundário: Acridinas/síntese química
Acridinas/química
Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Estrutura Molecular
Poli(ADP-Ribose) Polimerase-1/metabolismo
Inibidores de Poli(ADP-Ribose) Polimerases/síntese química
Inibidores de Poli(ADP-Ribose) Polimerases/química
Relação Estrutura-Atividade
Inibidores da Topoisomerase/síntese química
Inibidores da Topoisomerase/química
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acridines); 0 (Antineoplastic Agents); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Topoisomerase Inhibitors); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1); EC 5.99.1.- (DNA Topoisomerases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE


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[PMID]:28739698
[Au] Autor:Park Y; Son JY; Lee BM; Kim HS; Yoon S
[Ad] Endereço:School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
[Ti] Título:Highly Eribulin-resistant KBV20C Oral Cancer Cells Can Be Sensitized by Co-treatment with the Third-generation P-Glycoprotein Inhibitor, Elacridar, at a Low Dose.
[So] Source:Anticancer Res;37(8):4139-4146, 2017 08.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Eribulin mesylate, also called Halaven® (HAL), was recently developed as a microtubule-targeting drug and is used in the clinic for resistant or metastatic cancer. Previously, we showed that P-glycoprotein (P-gp)-overexpressing KBV20C oral cancer cells are highly resistant to HAL compared to sensitive KB cells. This qualitative study was designed to identify specific P-gp inhibitors that increase the sensitivity of highly resistant cancer cells to HAL. MATERIALS AND METHODS: In order to identify functional P-gp inhibitors, HAL-treated KBV20C cells were co-treated with P-gp inhibitors, verapamil, elacridar, cyclosporine A, mitotane, piperine, fumagillin, curcumin, indomethacin, probenecid, sulindac, tesmilifene, and C-4. We then evaluated which P-gp inhibitors required a low dose to sensitize KBV20C cells to HAL. We also determined whether a low dose of a P-gp inhibitor could inhibit P-gp efflux pumping. RESULTS: We found that cyclosporine A sensitized HAL-treated KBV20C cells at a low dose, whereas verapamil, another first-generation P-gp inhibitor, required a dose that was nearly 10-fold higher. We also found that the natural products, piperine and mitotane, sensitized KBV20C cells to HAL co-treatment. Interestingly, we found that elacridar, a third-generation P-gp inhibitor, sensitized HAL-treated cells at a low dose. Elacridar required approximately a 500-fold lower dose than that of verapamil to exert a similar effect. All inhibitors showed P-gp inhibitory activity that correlated with sensitivity to HAL. CONCLUSION: These results suggest that highly HAL-resistant cancer cells can be sensitized with cyclosporine A or elacridar, specific P-gp inhibitors that exert their effects at a low dose. These findings provide important information regarding the sensitization of highly HAL-resistant cells with selective P-gp inhibitors and indicate that elacridar may be used to treat such highly HAL-resistant cancer cells.
[Mh] Termos MeSH primário: Acridinas/administração & dosagem
Resistência a Medicamentos Antineoplásicos/genética
Furanos/administração & dosagem
Cetonas/administração & dosagem
Neoplasias Bucais/tratamento farmacológico
Tetra-Hidroisoquinolinas/administração & dosagem
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Sinergismo Farmacológico
Seres Humanos
Neoplasias Bucais/genética
Neoplasias Bucais/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Acridines); 0 (Furans); 0 (Ketones); 0 (Tetrahydroisoquinolines); LR24G6354G (eribulin); N488540F94 (Elacridar)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


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[PMID]:28657713
[Au] Autor:Charif R; Granotier-Beckers C; Bertrand HC; Poupon J; Ségal-Bendirdjian E; Teulade-Fichou MP; Boussin FD; Bombard S
[Ad] Endereço:Université Paris Descartes, INSERM UMR-S-1007, 45 rue des Saints-Pères, 75006 Paris, France.
[Ti] Título:Association of a Platinum Complex to a G-Quadruplex Ligand Enhances Telomere Disruption.
[So] Source:Chem Res Toxicol;30(8):1629-1640, 2017 Aug 21.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Telomeres protect the ends of chromosomes against illegitimate recombination and repair. They can be targets for G-quadruplex ligands and platinum complexes due to their repeated G-rich sequences. Protection of telomeres is ensured by a complex of six proteins, including TRF2, which inhibits the DNA damage response pathway. We analyzed telomere modifications induced in cancer cells by the experimental hybrid platinum complex, Pt-MPQ, comprising both an ethylene diamine monofunctional platinum complex and a G-quadruplex recognition moiety (MPQ). Pt-MPQ promotes the displacement of two telomeric proteins (TRF2 and TRF1) from telomeres, as well as the formation of telomere damage and telomere sister losses, whereas the control compound MPQ does not. This suggests that the platinum moiety potentiates the targeting of the G-quadruplex ligand to telomeres, opening a new perspective for telomere biology and anticancer therapy. Interestingly, the chemotherapy drug cisplatin, which has no specific affinity for G-quadruplex structures, partially induces the TRF2 delocalization from telomeres but produces less telomeric DNA damage, suggesting that this TRF2 displacement could be independent of G-quadruplex recognition.
[Mh] Termos MeSH primário: Complexos de Coordenação/toxicidade
Quadruplex G/efeitos dos fármacos
Platina/química
Telômero/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acridinas/toxicidade
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Cisplatino/toxicidade
Dano ao DNA/efeitos dos fármacos
Seres Humanos
Ligantes
Microscopia de Fluorescência
Compostos Organoplatínicos/toxicidade
Telômero/metabolismo
Encurtamento do Telômero/efeitos dos fármacos
Proteína 2 de Ligação a Repetições Teloméricas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acridines); 0 (Coordination Complexes); 0 (Ligands); 0 (Organoplatinum Compounds); 0 (Telomeric Repeat Binding Protein 2); 0 (platinum-mono-para-quinacridine); 49DFR088MY (Platinum); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.7b00131


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[PMID]:28544619
[Au] Autor:Sharma A; Piplani P
[Ad] Endereço:University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
[Ti] Título:Design and synthesis of some acridine-piperazine hybrids for the improvement of cognitive dysfunction.
[So] Source:Chem Biol Drug Des;90(5):926-935, 2017 Nov.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A novel series of hybrid molecules (5a-5m) was designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against cognitive dysfunction. Heterocyclic moieties acridine and piperazine were conjugated with suitable linkers in a single scaffold, and the structures of the target compounds were confirmed by IR, H NMR, C NMR, and LC-MS analysis. The pharmacological activity of synthesized compounds was evaluated using behavioral models of amnesia viz. step-down passive avoidance and elevated plus maze at a dose 0.5 mg/kg as compared to standard rivastigmine. In vitro acetylcholinesterase (AChE) inhibition studies using brain homogenate of mice as the enzyme source revealed that most of the compounds exhibited a significant ability to inhibit the enzyme cholinesterase with compound 5c being the most potent (IC 0.33 µm). Biochemical estimation of oxidative stress markers viz. plasma nitrite, thiobarbituric acid reactive substances, catalase, superoxide dismutase, and glutathione has been carried out using the respective assays to see the effect of the synthesized compounds on the scopolamine-induced oxidative damage. The molecular docking studies indicated the binding mode of the compounds to the catalytic site, peripheral site, and mid-gorge of AChE simultaneously. The calculated absorption, distribution, metabolism and excretion properties ensured the drug-likeness of the target compounds. The synthesized compounds were found to be potential cognitive enhancers, which were able to interfere with the scopolamine-induced oxidative stress also.
[Mh] Termos MeSH primário: Acridinas/química
Acridinas/uso terapêutico
Disfunção Cognitiva/tratamento farmacológico
Nootrópicos/química
Nootrópicos/uso terapêutico
Piperazinas/química
Piperazinas/uso terapêutico
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Acridinas/farmacologia
Animais
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Encéfalo/fisiopatologia
Inibidores da Colinesterase/química
Inibidores da Colinesterase/farmacologia
Inibidores da Colinesterase/uso terapêutico
Cognição/efeitos dos fármacos
Disfunção Cognitiva/metabolismo
Disfunção Cognitiva/fisiopatologia
Desenho de Drogas
Feminino
Camundongos
Simulação de Acoplamento Molecular
Nootrópicos/farmacologia
Estresse Oxidativo/efeitos dos fármacos
Piperazinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acridines); 0 (Cholinesterase Inhibitors); 0 (Nootropic Agents); 0 (Piperazines); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.13017


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[PMID]:28525838
[Au] Autor:Cui Z; Chen S; Wang Y; Gao C; Chen Y; Tan C; Jiang Y
[Ad] Endereço:The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Antitumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
[Ti] Título:Design, synthesis and evaluation of azaacridine derivatives as dual-target EGFR and Src kinase inhibitors for antitumor treatment.
[So] Source:Eur J Med Chem;136:372-381, 2017 Aug 18.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Overexpression of EGFR is often associated with advanced stage disease and poor prognosis. In certain cancers, Src works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and Src is of therapeutic advantage against these cancers. Based on molecular docking and our previous studies, we rationally designed a new series of azaacridine derivatives as potent EGFR and Src dual inhibitors. Most of the synthesized azaacridines displayed good antiproliferative activity against K562 and A549 cells. The representative compound 13b showed nM IC values against K562 and A549 cells, and inhibited EGFR at inhibition rate of 33.53% at 10 µM and Src at inhibition rate of 72.12% at 1 µM. Furthermore, compound 13b could inhibit the expression of EGFR, p-EGFR, Src and p-Src. Moreover, 13b efficiently inhibited the invasion of tumor cells and induced cancer cells apoptosis. Our study suggested that azaacridine scaffold can be developed as novel multi-target kinase inhibitors for cancer therapy.
[Mh] Termos MeSH primário: Acridinas/farmacologia
Antineoplásicos/farmacologia
Compostos Aza/farmacologia
Desenho de Drogas
Inibidores de Proteínas Quinases/farmacologia
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Quinases da Família src/antagonistas & inibidores
[Mh] Termos MeSH secundário: Acridinas/síntese química
Acridinas/química
Antineoplásicos/síntese química
Antineoplásicos/química
Apoptose/efeitos dos fármacos
Compostos Aza/síntese química
Compostos Aza/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Receptor do Fator de Crescimento Epidérmico/metabolismo
Relação Estrutura-Atividade
Quinases da Família src/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acridines); 0 (Antineoplastic Agents); 0 (Aza Compounds); 0 (Protein Kinase Inhibitors); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.2 (src-Family Kinases)
[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:170520
[St] Status:MEDLINE


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[PMID]:28511910
[Au] Autor:Li D; Yuan Z; Chen S; Zhang C; Song L; Gao C; Chen Y; Tan C; Jiang Y
[Ad] Endereço:Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering L
[Ti] Título:Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors.
[So] Source:Bioorg Med Chem;25(13):3437-3446, 2017 Jul 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC value of 0.57µM against U937 cells, which was slightly better than m-AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC of which was more than 3 times lower than m-AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50µM. The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway.
[Mh] Termos MeSH primário: Acridinas/farmacologia
Antineoplásicos/farmacologia
Compostos Aza/farmacologia
DNA Topoisomerases Tipo II/metabolismo
DNA/metabolismo
Inibidores da Topoisomerase II/metabolismo
Inibidores da Topoisomerase II/farmacologia
[Mh] Termos MeSH secundário: Acridinas/síntese química
Acridinas/química
Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/metabolismo
Apoptose/efeitos dos fármacos
Compostos Aza/síntese química
Compostos Aza/química
Sítios de Ligação
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
DNA/química
DNA Topoisomerases Tipo I/metabolismo
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Ligantes
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
Inibidores da Topoisomerase II/síntese química
Inibidores da Topoisomerase II/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acridines); 0 (Antineoplastic Agents); 0 (Aza Compounds); 0 (Ligands); 0 (Topoisomerase II Inhibitors); 9007-49-2 (DNA); EC 5.99.1.2 (DNA Topoisomerases, Type I); EC 5.99.1.3 (DNA Topoisomerases, Type II)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE



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