Base de dados : MEDLINE
Pesquisa : D03.132.032.077 [Categoria DeCS]
Referências encontradas : 86 [refinar]
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[PMID]:26029962
[Au] Autor:Gatti L; Perego P
[Ad] Endereço:a Molecular Pharmacology Unit; Department of Experimental Oncology and Molecular Medicine ; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan , Italy.
[Ti] Título:Orchestration of DSB repair: a novel BRCA2 connection.
[So] Source:Cell Cycle;14(14):2195-6, 2015.
[Is] ISSN:1551-4005
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Acronina/análogos & derivados
Antineoplásicos Alquilantes/metabolismo
Proteína BRCA2/metabolismo
Pontos de Checagem do Ciclo Celular/fisiologia
Reparo do DNA/fisiologia
[Mh] Termos MeSH secundário: Animais
Seres Humanos
[Pt] Tipo de publicação:COMMENT; NEWS
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 0 (BRCA2 Protein); QE0G097358 (Acronine)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:150716
[Lr] Data última revisão:
150716
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150602
[St] Status:MEDLINE
[do] DOI:10.1080/15384101.2015.1056614


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[PMID]:25945522
[Au] Autor:Rocca CJ; Soares DG; Bouzid H; Henriques JA; Larsen AK; Escargueil AE
[Ad] Endereço:a Laboratory of Cancer Biology and Therapeutics ; Centre de Recherche Saint-Antoine ; Paris , France.
[Ti] Título:BRCA2 is needed for both repair and cell cycle arrest in mammalian cells exposed to S23906, an anticancer monofunctional DNA binder.
[So] Source:Cell Cycle;14(13):2080-90, 2015.
[Is] ISSN:1551-4005
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Repair of DNA-targeted anticancer agents is an active area of investigation of both fundamental and clinical interest. However, most studies have focused on a small number of compounds limiting our understanding of both DNA repair and the DNA damage response. S23906 is an acronycine derivative that shows strong activity toward solid tumors in experimental models. S23906 forms bulky monofunctional DNA adducts in the minor groove which leads to destabilization of the double-stranded helix. We now report that S23906 induces formation of DNA double strand breaks that are processed through homologous recombination (HR) but not Non-Homologous End-Joining (NHEJ) repair. Interestingly, S23906 exposure was accompanied by a higher sensitivity of BRCA2-deficient cells compared to other HR deficient cell lines and by an S-phase accumulation in wild-type (wt), but not in BRCA2-deficient cells. Recently, we have shown that S23906-induced S phase arrest was mediated by the checkpoint kinase Chk1. However, its activated phosphorylated form is equally induced by S23906 in wt and BRCA2-deficient cells, likely indicating a role for BRCA2 downstream of Chk1. Accordingly, override of the S phase arrest by either 7-hydroxystaurosporine (UCN-01) or AZD7762 potentiates the cytotoxic activity of S23906 in wt, but not in BRCA2-deficient cells. Together, our findings suggest that the pronounced sensitivity of BRCA2-deficient cells to S23906 is due to both a defective S-phase arrest and the absence of HR repair. Tumors with deficiencies for proteins involved in HR, and BRCA2 in particular, may thus show increased sensitivity to S23906, thereby providing a rationale for patient selection in clinical trials.
[Mh] Termos MeSH primário: Acronina/análogos & derivados
Antineoplásicos Alquilantes/metabolismo
Proteína BRCA2/metabolismo
Pontos de Checagem do Ciclo Celular/fisiologia
Reparo do DNA/fisiologia
[Mh] Termos MeSH secundário: Acronina/metabolismo
Acronina/farmacologia
Animais
Antineoplásicos Alquilantes/farmacologia
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/fisiologia
Cricetinae
Reparo do DNA por Junção de Extremidades/efeitos dos fármacos
Reparo do DNA por Junção de Extremidades/fisiologia
Reparo do DNA/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1,2-diacetoxy-3,14-dihydro-3,3,14-trimethyl-6-methoxy-7H-benz(b)pyrano(3,2-d)acridin-7-one); 0 (Antineoplastic Agents, Alkylating); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); QE0G097358 (Acronine)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:160506
[Lr] Data última revisão:
160506
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150507
[St] Status:MEDLINE
[do] DOI:10.1080/15384101.2015.1042632


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[PMID]:25360689
[Au] Autor:Tian W; Yougnia R; Depauw S; Lansiaux A; David-Cordonnier MH; Pfeiffer B; Kraus-Berthier L; Léonce S; Pierré A; Dufat H; Michel S
[Ad] Endereço:Laboratoire de Pharmacognosie, Université Paris Descartes , U.M.R./C.N.R.S. n° 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75006 Paris, France.
[Ti] Título:Synthesis, antitumor activity, and mechanism of action of benzo[b]chromeno[6,5-g][1,8]naphthyridin-7-one analogs of acronycine.
[So] Source:J Med Chem;57(24):10329-42, 2014 Dec 26.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A series of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]chromeno[6,5-g][1,8]naphthyridin-7-one (4), 13-aza derivatives of benzo[b]acronycine, the isomeric 5-methoxy-2,2,13-trimethyl-2,13-dihydro-6H-benzo[b]chromeno[7,6-g][1,8]naphthyridin-6-one (5), and related cis-diols mono- and diesters were designed and synthesized. Their in vitro and in vivo biological activities were evaluated. As previously observed in the acronycine series, esters were the most potent derivatives exhibiting submicromolar activities; among them monoesters are particularly active. Racemic diacetate 21 showed a strong activity against KB-3-1 cell lines and was selected for in vivo evaluation and proved to be active, inhibiting tumor growth by more than 80%. After separation of the two enantiomers, compounds 21a and 21b were also evaluated against C38 colon adenocarcinoma; their activities were found to be significantly different.
[Mh] Termos MeSH primário: Acronina/química
Adenocarcinoma/tratamento farmacológico
Antineoplásicos/síntese química
Antineoplásicos/farmacologia
Carcinoma de Células Escamosas/tratamento farmacológico
Proliferação Celular/efeitos dos fármacos
Neoplasias do Colo/tratamento farmacológico
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia
Naftiridinas/síntese química
Naftiridinas/farmacologia
[Mh] Termos MeSH secundário: Adenocarcinoma/patologia
Animais
Carcinoma de Células Escamosas/patologia
Neoplasias do Colo/patologia
Desenho de Drogas
Ensaios de Seleção de Medicamentos Antitumorais
Ensaio de Desvio de Mobilidade Eletroforética
Seres Humanos
Concentração Inibidora 50
Camundongos
Camundongos Endogâmicos C57BL
Modelos Moleculares
Estrutura Molecular
Estereoisomerismo
Relação Estrutura-Atividade
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo(b)chromeno(6,5-g)(1,8)naphthyridin-7-one); 0 (Antineoplastic Agents); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Naphthyridines); QE0G097358 (Acronine)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141101
[St] Status:MEDLINE
[do] DOI:10.1021/jm500927d


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[PMID]:23409959
[Au] Autor:Lenglet G; Depauw S; Mendy D; David-Cordonnier MH
[Ad] Endereço:INSERM U837-JPARC, Team 4, IRCL, Place de Verdun, Lille 59045, France.
[Ti] Título:Protein recognition of the S23906-1-DNA adduct by nuclear proteins: direct involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
[So] Source:Biochem J;452(1):147-59, 2013 May 15.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In a view to develop new DNA alkylating antitumour drugs, evaluating the precise mechanism of action and the molecular/cellular consequences of the alkylation is a point of major interest. The benzo-b-acronycine derivative S23906-1 alkylates guanine nucleobases in the minor groove of the DNA helix and presents an original ability to locally open the double helix of DNA, which appears to be associated with its cytotoxic activity. However, the molecular mechanism linking adduct formation to cellular consequences is not precisely known. The objective of the present study was to identify proteins involved in the recognition and mechanism of action of S23906-DNA adducts. We found that GAPDH (glyceraldehyde-3-phosphate dehydrogenase) is a protein that binds to S23906-alkylated single-stranded, double-stranded and telomeric sequences in a drug-dependent and DNA sequence/structure-dependent manner. We used the CASTing (cyclic amplification of sequence targeting) method to identify GAPDH DNA-binding selectivity and then evaluated its binding to such selected S23906-alkylated sequences. At the cellular level, alkylation of S23906-1 results in an increase in the binding of GAPDH and its protein partner HMG (high-mobility group) B1 to the chromatin. Regarding the multiple roles of GAPDH in apoptosis and DNA repair, the cytotoxic and apoptotic activities of GAPDH were evaluated and present opposite effects in two different cellular models.
[Mh] Termos MeSH primário: Acronina/análogos & derivados
Adutos de DNA/química
Gliceraldeído-3-Fosfato Desidrogenases/química
Proteínas Nucleares/química
[Mh] Termos MeSH secundário: Acronina/química
Alquilação
Adutos de DNA/genética
Adutos de DNA/metabolismo
Proteínas de Ligação a DNA/química
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Gliceraldeído-3-Fosfato Desidrogenases/genética
Gliceraldeído-3-Fosfato Desidrogenases/metabolismo
Células HT29
Seres Humanos
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Ligação Proteica/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA Adducts); 0 (DNA-Binding Proteins); 0 (Nuclear Proteins); 0 (S 23906-1); EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases); QE0G097358 (Acronine)
[Em] Mês de entrada:1306
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130216
[St] Status:MEDLINE
[do] DOI:10.1042/BJ20120860


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[PMID]:21470188
[Au] Autor:Soares DG; Battistella A; Rocca CJ; Matuo R; Henriques JA; Larsen AK; Escargueil AE
[Ad] Endereço:Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris 75571, France.
[Ti] Título:Ataxia telangiectasia mutated- and Rad3-related kinase drives both the early and the late DNA-damage response to the monofunctional antitumour alkylator S23906.
[So] Source:Biochem J;437(1):63-73, 2011 Jul 01.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Numerous anticancer agents and environmental mutagens target DNA. Although all such compounds interfere with the progression of the replication fork and inhibit DNA synthesis, there are marked differences in the DNA-damage response pathways they trigger, and the relative impact of the proximal or the distal signal transducers on cell survival is mainly lesion-specific. Accordingly, checkpoint kinase inhibitors in current clinical development show synergistic activity with some DNA-targeting agents, but not with others. In the present study, we characterize the DNA-damage response to the antitumour acronycine derivative S23906, which forms monofunctional adducts with guanine residues in the minor groove of DNA. S23906 exposure is accompanied by specific recruitment of RPA (replication protein A) at replication sites and rapid Chk1 activation. In contrast, neither MRN (Mre11-Rad50-Nbs1) nor ATM (ataxia-telangiectasia mutated), contributes to the initial response to S23906. Interestingly, genetic attenuation of ATR (ATM- and Ras3-related) activity inhibits not only the early phosphorylation of histone H2AX and Chk1, but also interferes with the late phosphorylation of Chk2. Moreover, loss of ATR function or pharmacological inhibition of the checkpoint kinases by AZD7762 is accompanied by abrogation of the S-phase arrest and increased sensitivity towards S23906. These findings identify ATR as a central co-ordinator of the DNA-damage response to S23906, and provide a mechanistic rationale for combinations of S23906 and similar agents with checkpoint abrogators.
[Mh] Termos MeSH primário: Acronina/análogos & derivados
Antineoplásicos Alquilantes/farmacologia
Proteínas de Ciclo Celular/fisiologia
Dano ao DNA
Mutação
Proteínas Serina-Treonina Quinases/fisiologia
[Mh] Termos MeSH secundário: Acronina/farmacologia
Proteínas Mutadas de Ataxia Telangiectasia
Proteínas de Ciclo Celular/genética
Proteínas de Ciclo Celular/metabolismo
Quinase do Ponto de Checagem 1
Quinase do Ponto de Checagem 2
Enzimas Reparadoras do DNA/metabolismo
Proteínas de Ligação a DNA/metabolismo
Células HeLa
Histonas/metabolismo
Seres Humanos
Proteína Homóloga a MRE11
Microscopia de Fluorescência
Proteínas Nucleares/metabolismo
Proteínas Quinases/metabolismo
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Proteína de Replicação A/metabolismo
Tiofenos/farmacologia
Ureia/análogos & derivados
Ureia/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (1,2-diacetoxy-3,14-dihydro-3,3,14-trimethyl-6-methoxy-7H-benz(b)pyrano(3,2-d)acridin-7-one); 0 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide); 0 (Antineoplastic Agents, Alkylating); 0 (Cell Cycle Proteins); 0 (DNA-Binding Proteins); 0 (H2AFX protein, human); 0 (Histones); 0 (MRE11A protein, human); 0 (NBN protein, human); 0 (Nuclear Proteins); 0 (Rad50 protein, human); 0 (Replication Protein A); 0 (Thiophenes); 8W8T17847W (Urea); EC 2.7.- (Protein Kinases); EC 2.7.1.11 (Checkpoint Kinase 2); EC 2.7.11.1 (ATR protein, human); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins); EC 2.7.11.1 (CHEK1 protein, human); EC 2.7.11.1 (CHEK2 protein, human); EC 2.7.11.1 (Checkpoint Kinase 1); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 3.1.- (MRE11 Homologue Protein); EC 6.5.1.- (DNA Repair Enzymes); QE0G097358 (Acronine)
[Em] Mês de entrada:1108
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110408
[St] Status:MEDLINE
[do] DOI:10.1042/BJ20101770


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[PMID]:21411193
[Au] Autor:Gaslonde T; Covello F; Velazquez-Alonso L; Léonce S; Pierré A; Pfeiffer B; Michel S; Tillequin F
[Ad] Endereço:Laboratoire de Pharmacognosie, Université Paris Descartes, UMR/CNRS 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75006 Paris, France. thomas.gaslonde@parisdescartes.fr
[Ti] Título:Synthesis and cytotoxic activity of benzo[a]acronycine and benzo[b]acronycine substituted on the A ring.
[So] Source:Eur J Med Chem;46(5):1861-73, 2011 May.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The impact of substitutions at position 10 in the A ring of the cytotoxic benzo[a]acronycine and benzo[b]acronycine series has been explored. 10-Bromobenzo[a] and 10-bromobenzo[b]acronycine were prepared in 12% and 15% yield respectively from commercially available chemicals. Their 1,2-dihydro-1,2-dihydroxy diesters were synthesized. The different derivatives were tested against two cell lines KB-3-1 and L1210. Their cytotoxic activities were found in the same range of magnitude as their non-substituted counterparts. These structure-activity relationships permitted to conclude that the introduction of a substituent at position 10 maintains the activity in both the benzo[a] and [b]acronycine series and open the way to further pharmacomodulations.
[Mh] Termos MeSH primário: Acronina/análogos & derivados
Antineoplásicos/farmacologia
[Mh] Termos MeSH secundário: Acronina/síntese química
Acronina/química
Acronina/farmacologia
Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Camundongos
Estrutura Molecular
Estereoisomerismo
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (benzo(b)acronycine); QE0G097358 (Acronine)
[Em] Mês de entrada:1108
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110318
[St] Status:MEDLINE
[do] DOI:10.1016/j.ejmech.2011.02.050


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[PMID]:20399198
[Au] Autor:Rocca CJ; Poindessous V; Soares DG; Ouadrani KE; Sarasin A; Guérin E; de Gramont A; Henriques JA; Escargueil AE; Larsen AK
[Ad] Endereço:Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris 75571, France.
[Ti] Título:The NER proteins XPC and CSB, but not ERCC1, regulate the sensitivity to the novel DNA binder S23906: implications for recognition and repair of antitumor alkylators.
[So] Source:Biochem Pharmacol;80(3):335-43, 2010 Aug 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:S23906 belongs to a novel class of alkylating anticancer agents forming bulky monofunctional DNA adducts. A unique feature of S23906 is its "helicase-like" activity leading to the destabilization of the surrounding duplex DNA. We here characterize the recognition and repair of S23906 adducts by the nucleotide excision repair (NER) machinery. All NER-deficient human cell lines tested showed increased sensitivity to S23906, which was particularly pronounced for cells deficient in XPC, CSB and XPA. In comparison, deficiencies in ERCC1 or XPF had lesser impact on the sensitivity to S23906. The sensitivity was, at least in part, linked to the conversion of unrepaired adducts into toxic DNA strand breaks as shown by single cell electrophoresis and gamma-H2AX formation. The pharmacological relevance of these findings was confirmed by the characterization of KB carcinoma cells with acquired S23906 resistance. These cells showed increased NER activity in vivo as well as toward damaged plasmid DNA in vitro. In particular, both global genome NER, as shown by unscheduled DNA synthesis, and transcription-coupled NER, as shown by transcriptional recovery, were up-regulated in the S23906-resistant cells. The increased NER activity was accompanied by up to 5-fold up-regulation of XPC, CSB and XPA proteins without detectable alterations of ERCC1 on the DNA, RNA or protein levels. Our results suggest that S23906 adducts are recognized and repaired by both NER sub-pathways in contrast to other members of this class, that are only recognized by transcription-coupled NER. We further show that NER activity can be up-regulated without changes in ERCC1 expression.
[Mh] Termos MeSH primário: Acronina/farmacologia
Antineoplásicos Alquilantes/metabolismo
DNA Helicases/fisiologia
Enzimas Reparadoras do DNA/fisiologia
Proteínas de Ligação a DNA/fisiologia
DNA/metabolismo
Endonucleases/fisiologia
[Mh] Termos MeSH secundário: Acronina/metabolismo
Alquilantes/química
Alquilantes/metabolismo
Antineoplásicos Alquilantes/química
Sítios de Ligação/fisiologia
Linhagem Celular
Linhagem Celular Tumoral
Adutos de DNA/metabolismo
Seres Humanos
Receptores X do Fígado
Receptores Nucleares Órfãos/deficiência
Receptores Nucleares Órfãos/fisiologia
Proteínas de Ligação a Poli-ADP-Ribose
Xeroderma Pigmentoso/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Alkylating Agents); 0 (Antineoplastic Agents, Alkylating); 0 (DNA Adducts); 0 (DNA-Binding Proteins); 0 (Liver X Receptors); 0 (Orphan Nuclear Receptors); 0 (Poly-ADP-Ribose Binding Proteins); 156533-34-5 (XPC protein, human); 9007-49-2 (DNA); EC 3.1.- (ERCC1 protein, human); EC 3.1.- (Endonucleases); EC 3.6.4.- (DNA Helicases); EC 3.6.4.12 (ERCC6 protein, human); EC 6.5.1.- (DNA Repair Enzymes); QE0G097358 (Acronine)
[Em] Mês de entrada:1006
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100420
[St] Status:MEDLINE
[do] DOI:10.1016/j.bcp.2010.04.012


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[PMID]:19926174
[Au] Autor:Boutefnouchet S; Minh NT; Putrus R; Pfeiffer B; Léonce S; Pierré A; Michel S; Tillequin F; Lallemand MC
[Ad] Endereço:Laboratoire de Pharmacognosie de l'Université Paris Descartes, UMR/CNRS n degrees 8638, Faculté de Pharmacie, 4 Avenue de l'Observatoire, 75006 Paris, France.
[Ti] Título:Synthesis and cytotoxic activity of psorospermin and acronycine analogues in the 3-propyloxy-acridin-9(10H)-one and -benzo[b]acridin-125H-one series.
[So] Source:Eur J Med Chem;45(2):581-7, 2010 Feb.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:In order to explore the structure-activity relationships in the acronycine and psorospermin series, simplified analogues of the highly cytotoxic (+/-)-(2R*,1'R*)-5-methoxy-11-methyl-2-(2-methyloxiran-2-yl)-1,2-dihydro-11H-furo[2,3-c]acridin-6-one and (+/-)-(2R*,1'R*)-5-methoxy-13-methyl-2-(2-methyloxiran-2-yl)-1,2-dihydro-13H-benzo[b]furo[3,2-h]-acridin-6-one lacking the fused furan ring, including 3-allyloxy-1-methoxy-10-methyl-acridin-9(10H)-one, 3-allyloxy-1-methoxy-5-methyl-benzo[b]acridin-12(5H)-one, the corresponding epoxides, and related dihydrodiol esters and diesters were prepared. Only the simplified oxirane compounds displayed significant antiproliferative activity compared to the parent compounds. The oxirane alkylating unit appears indispensible to observe significant antiproliferative activity in both series, but the presence of the angularly fused furan ring does not appear as a crucial structural requirement to observe significant cytotoxic activity.
[Mh] Termos MeSH primário: Acronina/análogos & derivados
Acronina/farmacologia
Antineoplásicos/química
Antineoplásicos/farmacologia
Xantonas/química
[Mh] Termos MeSH secundário: Acronina/síntese química
Animais
Antineoplásicos/síntese química
Linhagem Celular Tumoral
Seres Humanos
Concentração Inibidora 50
Camundongos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Xanthones); 74045-97-9 (psorospermin); QE0G097358 (Acronine)
[Em] Mês de entrada:1004
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:091121
[St] Status:MEDLINE
[do] DOI:10.1016/j.ejmech.2009.10.045


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[PMID]:19758748
[Au] Autor:Cahuzac N; Studény A; Marshall K; Versteege I; Wetenhall K; Pfeiffer B; Léonce S; Hickman JA; Pierré A; Golsteyn RM
[Ad] Endereço:Institut de Recherches Servier, Cancer Research Division, Croissy-sur Seine, France.
[Ti] Título:An unusual DNA binding compound, S23906, induces mitotic catastrophe in cultured human cells.
[So] Source:Cancer Lett;289(2):178-87, 2010 Mar 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:The biochemical pathways that lead cells to mitotic catastrophe are not well understood. To identify these pathways, we have taken an approach of treating cells with a novel genotoxic compound and characterizing whether cells enter mitotic catastrophe or not. S23906 is a novel acronycine derivative that forms adducts with the N2 residue of guanine in the minor groove of the DNA helix and destabilizes base pairing to cause helix opening. We observed, in HeLa and HT-29 cells, that S23906 induced gamma-H2AX and activated checkpoint kinase 1, as did bleomycin, camptothecin, and cisplatin, when tested under equi-toxic conditions. S23906 also induced cyclin E1 protein, although this activity was not required for cytotoxicity because knock down of cyclin E1 by RNA interference did not affect the number of dead cells after treatment. Cyclin B1 levels first decreased and then increased after treatment with S23906. Cyclin B1 was associated with Cdk1 kinase activity, which correlated with an increase in the number of mitotic cells. By 32 h after treatment, at least 20% of the cells entered mitotic catastrophe as determined by microscopy. Suppression of the DNA checkpoint response by co-treatment with caffeine increased the number of cells in mitosis. These results suggest that mitotic catastrophe is one of the cellular responses to S23906 and that mitotic catastrophe may be a common cellular response to many different types of DNA damage.
[Mh] Termos MeSH primário: Acronina/análogos & derivados
DNA/metabolismo
Mitose/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acronina/farmacologia
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Northern Blotting
Proteína Quinase CDC2/metabolismo
Cafeína/farmacologia
Ciclina B1/metabolismo
Ciclina E/antagonistas & inibidores
Ciclina E/genética
Ciclina E/metabolismo
Imunofluorescência
Células HT29
Células HeLa
Seres Humanos
Proteínas Oncogênicas/antagonistas & inibidores
Proteínas Oncogênicas/genética
Proteínas Oncogênicas/metabolismo
RNA Interferente Pequeno/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (CCNE1 protein, human); 0 (Cyclin B1); 0 (Cyclin E); 0 (Oncogene Proteins); 0 (RNA, Small Interfering); 0 (S 23906-1); 3G6A5W338E (Caffeine); 9007-49-2 (DNA); EC 2.7.11.22 (CDC2 Protein Kinase); QE0G097358 (Acronine)
[Em] Mês de entrada:1004
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090918
[St] Status:MEDLINE
[do] DOI:10.1016/j.canlet.2009.08.014


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[PMID]:19752199
[Au] Autor:Depauw S; Gaslonde T; Léonce S; Kraus-Berthier L; Laine W; Lenglet G; Chiaroni A; Pfeiffer B; Bailly C; Michel S; Tillequin F; Pierré A; David-Cordonnier MH
[Ad] Endereço:INSERM-U837, Centre de Recherches Jean-Pierre Aubert (JPARC), Team-4 "Molecular and Cellular Targeting for Cancer Treatment," Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille, France.
[Ti] Título:Influence of the stereoisomeric position of the reactive acetate groups of the benzo[b]acronycine derivative S23906-1 on its DNA alkylation, helix-opening, cytotoxic, and antitumor activities.
[So] Source:Mol Pharmacol;76(6):1172-85, 2009 Dec.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:S23906-1 is a benzo[b]acronycine derivative acting as a DNA-alkylating agent through covalent bonding to the exocyclic amino group of guanines and subsequent local opening of the DNA helix. This compound was selected for phase I clinical trials based on its efficient antitumor activity in experimental models and its unique mode of action. S23906-1 is the racemate of cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one. Here, we evaluated the cytotoxic and antitumor activities of the two pure cis-enantiomers and investigated the mechanism of action of both cis- and trans-racemates and their enantiomers in terms of DNA alkylation potency and locally drug-induced DNA helix opening process. Reaction with glutathione, as a detoxification process, was also studied. The trans-compounds, both as racemate or separated enantiomers, were found less potent than the corresponding cis-derivatives. Among the cis-enantiomers, the most efficient one regarding DNA alkylation bears the acetate on the reactive C1 position in the R configuration, both on purified DNA and genomic DNA extracted from cell cultures. By contrast, the most cytotoxic and tumor-active enantiomer bears the C1-acetate in the S configuration. Distinct cellular DNA-alkylation levels or covalent bonding to glutathione could not explain the differences. However, we showed that the S and R orientations of the acetate on C1 asymmetric carbon lead to different local opening of the DNA, as visualized using nuclease S1 mapping. These different interactions could lead to modulated DNA-repair, protein/DNA interaction, and apoptosis processes.
[Mh] Termos MeSH primário: Acronina/análogos & derivados
Antineoplásicos Alquilantes/farmacologia
Citotoxinas/farmacologia
Substâncias Intercalantes/farmacologia
[Mh] Termos MeSH secundário: Acronina/química
Acronina/farmacologia
Animais
Antineoplásicos Alquilantes/química
Domínio Catalítico
Divisão Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Citotoxinas/química
Adutos de DNA/metabolismo
Seres Humanos
Substâncias Intercalantes/química
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos DBA
Neoplasias Experimentais/tratamento farmacológico
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 0 (Cytotoxins); 0 (DNA Adducts); 0 (Intercalating Agents); 0 (S 23906-1); QE0G097358 (Acronine)
[Em] Mês de entrada:0912
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090916
[St] Status:MEDLINE
[do] DOI:10.1124/mol.109.057554



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