RESUMO
The monoalkyltriazene moiety lends itself well to the design of combi-molecules. However, due to its instability under physiological conditions, efforts were directed towards stabilizing it by grafting a hydrolysable carbamate onto the 3-position. The synthesis and biological activities of these novel N-carbamyl triazenes are described.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Receptores ErbB/metabolismo , Receptor ErbB-2/metabolismo , Triazenos/química , Triazenos/farmacologia , Animais , Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Feminino , Humanos , Camundongos , Modelos Moleculares , Células NIH 3T3 , Ligação Proteica , Triazenos/síntese químicaRESUMO
According to the "combi-targeting" concept, the EGFR tyrosine kinase (TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds (3'-Cl and Br series) with small angles (0.5-3 degrees ) were generally stronger EGFR TK inhibitors than those with large angles (18-21 degrees ). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC(50) values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line (Pearson r = 0.8). On the basis of stability (t(1/2)), EGFR TK inhibitory potency (IC(50)), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.
Assuntos
Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Etilnitrosoureia/análogos & derivados , Compostos de Nitrosoureia/síntese química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Estabilidade de Medicamentos , Etilnitrosoureia/síntese química , Etilnitrosoureia/química , Etilnitrosoureia/farmacologia , Ligantes , Camundongos , Modelos Moleculares , Conformação Molecular , Células NIH 3T3 , Compostos de Nitrosoureia/química , Compostos de Nitrosoureia/farmacologia , Receptor ErbB-2/genética , Relação Estrutura-Atividade , Termodinâmica , TransfecçãoRESUMO
The synthesis of 6-(2-chloroethylamino)-4-anilinoquinazolines ZR2002 and ZR2003 designed to block EGFR tyrosine kinase and to damage genomic DNA is described. These compounds present fluorescence properties that permitted the quantitation of their subcellular uptake by flow cytometry. Fluorescence intensities increased with increasing levels of EGFR in a panel of isogenic and established cell lines.
Assuntos
Antineoplásicos Alquilantes/síntese química , Receptores ErbB/antagonistas & inibidores , Compostos de Mostarda Nitrogenada/síntese química , Quinazolinas/síntese química , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/química , Citometria de Fluxo , Fluorescência , Humanos , Concentração Inibidora 50 , Proteínas de Neoplasias/antagonistas & inibidores , Compostos de Mostarda Nitrogenada/química , Compostos de Mostarda Nitrogenada/farmacologia , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis and abl tyrosine kinase inhibitory activities of alkyltriazenes conjugated to phenylaminopyrimidines are described. Significant abl inhibitory activities were observed only when a benzamido spacer was inserted between the 1,2,3-triazene chain and the 2-phenyaminopyridopyrimidine moiety.