RESUMO
In this research, N-(2-aminoethyl)glycine-linked C-10 non-acetal deoxoartemisinin dimers were synthesized by using solution phase peptide synthesis approach. In addition, chemical modification of the C-10 non-acetal deoxoartemisinin monomers and dimers by adding a lysine unit to the N-terminus has been performed. The biological activities of all synthesized compounds were evaluated against the colon cancer cell line (Caco-2). The non-acetal deoxoartemisinin monomers 12a, 15a-c and dimers 13a, 16a-c were active against Caco-2 cells and more potent than dihydroartemisinin.
Assuntos
Acetais/farmacologia , Antineoplásicos/farmacologia , Artemisininas/farmacologia , Acetais/síntese química , Acetais/química , Antineoplásicos/síntese química , Antineoplásicos/química , Artemisininas/síntese química , Artemisininas/química , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The aim of this study was to investigate the influence of dendrimer surface properties on cellular internalization and intracellular trafficking in the human colon adenocarcinoma HT-29 cell line. Third-generation (G3) polyamidoamine (PAMAM) dendrimers were modified to contain either two lauroyl chains (G3L2), two propranolol molecules (G3P2), or two lauroyl and two propranolol molecules (G3L2P2) at the dendrimer surface. Surface-modified and unmodified dendrimers were labeled with fluorescein isothiocyanate (FITC) at an average molar ratio of 1:1. The mechanisms of cellular internalization and intracellular trafficking of dendrimers were analyzed by confocal laser scanning microscopy and flow cytometry. The internalization of G3 and G3P2 dendrimers involved both caveolae-dependent endocytosis and macropinocytosis pathways; internalization of G3L2P2 dendrimer appeared to involve caveolae-dependent, and possibly clathrin-dependent, endocytosis pathways; and internalization of G3L2 dendrimer occurred via caveolae-dependent, clathrin-dependent, and macropinocytosis pathways. Subcellular colocalization data indicated that unmodified and all surface-modified G3 PAMAM dendrimers were internalized and trafficked to endosomes and lysosomes. It is therefore apparent that the initial mode of dendrimer internalization into HT-29 cells is influenced by the surface properties of G3 PAMAM dendrimer.
