RESUMEN
A simple general synthesis of 1-aryl-6-azaisocytosine-5-carbonitriles 4 is described. This method is based on coupling diazonium salts with cyanoacetylcyanamide 2 and then cyclization of the formed 2-arylhydrazono-2-cyanoacetylcyanamides 3. The 6-azaisocytosines 4 were studied with respect to tautomeric equilibrium and the transformation of functional groups, and used in the synthesis of the condensed heterocyclic compounds: Purine isosteric imidazo[2,1-c]-[1,2,4]triazine 8 and the 1,2,4-triazino[2,3-a]quinazolines 9-12.
Asunto(s)
Citosina/química , Pirimidinas/síntesis química , Triazinas/síntesis química , Ciclización , Estructura Molecular , Pirimidinas/química , Triazinas/químicaRESUMEN
In this paper we describe the preparation of some derivatives of 1,2,4-triazino[4,5-a]benzimidazol-1-ones (5 and 6), containing additional benzimidazole ring. These compounds were prepared using coupling reactions of diazonium salts with 1,1-bis(1-ethoxycarbonyl-benzimidazol-2-yl)methane (2) to obtain unstable hydrazones 4, which readily undergo cyclization. Interestingly, the selected compounds demonstrated preferential cytotoxic activities against human carcinoma and glioma cell lines compared with leukemic cells. They showed significant activity against multidrug-resistant P-glycoprotein expressing cell lines but had less effect on multidrug-resistance protein 1 positive and topoisomerase IIalpha negative leukemias.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Antineoplásicos/química , Antineoplásicos/toxicidad , Bencimidazoles/química , Bencimidazoles/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Sensibilidad y EspecificidadRESUMEN
In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.
Asunto(s)
Compuestos Azo/síntesis química , Compuestos Azo/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Antimetabolitos , Bromodesoxiuridina , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Humanos , Immunoblotting , Modelos Moleculares , ARN/biosíntesis , ARN/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción Reversa/efectos de los fármacos , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A series of the 3,7-diaryl-5-(3,4,5-trimethoxyphenyl)pyrazolo[4,3-e][1,2,4]triazines have been synthesized in five steps. The cytotoxic activity of all of the newly synthesized compounds has been tested in vitro against five cancer cell lines. Several compounds demonstrated significant broad cytotoxic activity in low micromolar range, while others were selectively active against lung adenocarcinoma cell line A549.
Asunto(s)
Antineoplásicos/química , Triazinas/síntesis química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pirazoles , Relación Estructura-Actividad , Triazinas/farmacologíaRESUMEN
The 1H,13C and 15N NMR spectra of the reduction product of 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)benzene diazonium salt with sodium sulfite were measured and analysed. It is shown that the reaction product corresponds to 1-(indazol-3-yl)-1,2-dihydro-benzimidazol-2-on and not 6H-quinoxalino[1,2-c] [1,2,3]benzotriazin-12(13H)-one as published previously. The correctness of the structure was confirmed by an independent synthesis. The observed 15N chemical shifts were compared with the predicted ones using the ACD/NNMR 9.01 program.