RESUMO
Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded a novel series of potent farnesyltransferase inhibitors.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Quinolonas/farmacologia , Antineoplásicos/química , Inibidores Enzimáticos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Quinolonas/químicaRESUMO
Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos/síntese química , Quinolonas/síntese química , Quinolonas/farmacologia , Triazóis/síntese química , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Cinética , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Quinolonas/administração & dosagem , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase , Cinética , Conformação Molecular , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/farmacologia , Relação Estrutura-AtividadeAssuntos
Sinais de Localização Nuclear/metabolismo , Biblioteca de Peptídeos , Peptídeos/metabolismo , Alquil e Aril Transferases/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Divisão Celular , Membrana Celular/química , Membrana Celular/metabolismo , Citoplasma/química , Citoplasma/metabolismo , Avaliação Pré-Clínica de Medicamentos , Farnesiltranstransferase , Técnicas Genéticas , Proteínas de Fluorescência Verde , Humanos , Imuno-Histoquímica , Proteínas Luminescentes , Dados de Sequência Molecular , Mutação , Sinais de Localização Nuclear/química , Sinais de Localização Nuclear/genética , Peptídeos/química , Peptídeos/genética , Fenótipo , Polilisina/química , Polilisina/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Células Tumorais CultivadasRESUMO
PURPOSE: Inhibitors of farnesyltransferase (e.g., R115777) are being developed for therapy and prevention of various cancers. The efficacy of R115777 [Zarnestra; (B)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone] to prevent the development of lung tumors in mice was determined. EXPERIMENTAL DESIGN: Female strain A mice (7-8 weeks of age) were given 100 mg/kg benzo(a)pyrene [B(a)P] by i.p. injection, and 4 or 14 weeks later, they were given 50 or 100 mg/kg R115777 by oral gavage 5 days/week. The mice were sacrificed 22 weeks after they received the B(a)P. RESULTS: Tumor multiplicity was 5.0 +/- 0.85, 4.5 +/- 0.52, 2.1 +/- 0.31, and 1.5 +/- 0.31 tumors/mouse in mice that received 0, 50, 100 (weeks 4-22), or 100 (weeks 14-22) mg/kg R115777. Thus, 100 mg/kg R115777 was similarly effective in preventing lung tumors when administered during the promotional phase of carcinogenesis [that is, either 4 or 14 weeks after B(a)P], whereas the lower dose of 50 mg/kg R115777 was ineffective. The proliferating cell nuclear antigen labeling index was also significantly reduced in lung tumors from mice treated with 100 mg/kg R115777 starting at 4 or 14 weeks. CONCLUSIONS: These results demonstrated that R115777 can prevent the development of lung tumors in the A/J mouse model, where tumors routinely have mutations in the Ki-Rasoncogene.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/prevenção & controle , Quinolonas/uso terapêutico , Animais , Benzo(a)pireno/toxicidade , Quimioprevenção , Inibidores Enzimáticos/uso terapêutico , Feminino , Neoplasias Pulmonares/induzido quimicamente , Camundongos , Camundongos Endogâmicos ARESUMO
The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/síntese química , Azepinas/síntese química , Quinazolinas/química , Quinolonas/química , Animais , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Farnesiltranstransferase , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Quinazolinas/síntese química , Quinazolinas/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The naturally occurring cyclic tetrapeptide chlamydocin is a very potent inhibitor of cell proliferation. Here we show that chlamydocin is a highly potent histone deacetylase (HDAC) inhibitor, inhibiting HDAC activity in vitro with an IC(50) of 1.3 nM. Like other HDAC inhibitors, chlamydocin induces the accumulation of hyperacetylated histones H3 and H4 in A2780 ovarian cancer cells, increases the expression of p21(cip1/waf1), and causes an accumulation of cells in G(2)/M phase of the cell cycle. In addition, chlamydocin induces apoptosis by activating caspase-3, which in turn leads to the cleavage of p21(cip1/waf1) into a 15-kDa breakdown product and drives cells from growth arrest into apoptosis. Concomitant with the activation of caspase-3 and cleavage of p21(cip1/waf1), chlamydocin decreases the protein level of survivin, a member of the inhibitor of apoptosis protein family that is selectively expressed in tumors. Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors, stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21(cip1/waf1) induced by chlamydocin treatment. The decrease of survivin protein level is mediated by degradation via proteasomes since it can be inhibited by specific proteasome inhibitors. Taken together, our results show that induction of apoptosis by chlamydocin involves caspase-dependent cleavage of p21(cip1/waf1), which is strikingly associated with proteasome-mediated degradation of survivin.
Assuntos
Apoptose/efeitos dos fármacos , Cisteína Endopeptidases/fisiologia , Inibidores de Histona Desacetilases , Proteínas Associadas aos Microtúbulos/metabolismo , Complexos Multienzimáticos/fisiologia , Peptídeos Cíclicos/farmacologia , Apoptose/fisiologia , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Células HeLa , Histona Desacetilases/metabolismo , Humanos , Proteínas Inibidoras de Apoptose , Células K562 , Proteínas de Neoplasias , Peptídeos Cíclicos/química , Complexo de Endopeptidases do Proteassoma , Survivina , Células Tumorais CultivadasRESUMO
During the course of a screening program intended to identify new antiproliferative agents, a new bafilolide metabolite was discovered. R176502 (1) was isolated from the liquid fermentation cultures of a novel Micromonospora species found in African river bottom sediment. It was purified from ethyl acetate extracts using a series of countercurrent chromatographic steps. The structure was determined using 1- and 2-D NMR experiments. Three previously described bafilomycins (bafilomycins A1 (2), B1 (3), and B2 (4)) were also isolated (from other microbial strains). R176502 exhibited potency for inhibition of tumor cell proliferation in the nM range of concentrations.
Assuntos
Antineoplásicos/isolamento & purificação , Macrolídeos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Fermentação , Humanos , Macrolídeos/química , Macrolídeos/farmacologia , Micromonospora , Relação Estrutura-AtividadeRESUMO
Biological assay guided fractionation of a dichloromethane extract of Synaptolepis kirkii led to the isolation of four new and five known daphnane-type diterpene orthoesters, whose structure was established by spectroscopic data. Full spectroscopic data of the new and known natural products are reported here for the first time. Pronounced neurotrophic and substantial antileukaemia activities of these compounds were found in in vitro assays.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Fatores de Crescimento Neural/isolamento & purificação , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológico , Modelos Moleculares , Estrutura Molecular , Fatores de Crescimento Neural/química , Fatores de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Terpenos/química , Terpenos/isolamento & purificação , Terpenos/farmacologia , Thymelaeaceae/química , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Células Tumorais CultivadasRESUMO
General screening for inhibitors of microvessel growth in vitro in the rat aortic ring assay led to the discovery of a novel series of thiadiazole pyridazine compounds with potential anti-angiogenic activity. Chemical optimization produced orally active compounds with potent in vitro and in vivo anti-angiogenesis and anti-tumor activities.