Síntese e avaliação da atividade citotóxica de compostos nitroaromáticos

Abstract

In a recent study the cytotoxic activity of a series of nitro aromatic compounds were evaluated against cancer cell lines in vitro. The amides N-[4(chloromethyl)-3-nitrobenzoyl]morpholine and 4-(chloromethyl)-3-nitro-Npropylbenzamide showed significant activity and selectivity to hypoxic cells. In this work we describe the synthesis of several analogues of these hit compounds by ring substituent variations and variation of benzene ring by heterocyclic rings to generate more potent and selective compounds, with structural diversity. Quinoline and indol rings were synthesized using classical reactions of heterocyclic chemistry. For ring substituents and other positions, reactions like nitration, Mannich, bromination, fluorination and esterification were conducted. The synthesized analogues were assessed in vitro against three cancer cell lines: MDA-MB (breast adenocarcinoma), MCF-7 (breast adenocarcinoma estrogen-dependent) e HCT (colorectal carcinoma). The experiments were conducted at normoxia (2D culture) and hypoxia model (3D culture). The toxicity to normal cells (VERO) was also evaluated to determine the selectivity index (SI). Among the tested compounds, the quinoline 5, dinitrated derivative 18 and amide 31 were found to be active. Despite not exhibit selectivity to hypoxia model, these compounds are promising as antitumor agents per se, with IC50 values in low micromolar range and SI 4. Although nitroindoles 42, 44 and 47 and nitroquinoline 4 displayed low potency, these compounds were more selective to hypoxia model compared to normoxia. The obtained results provide new insights to the design of nitrobenzylic compounds and can be useful for planning novel analogues in the development of new classes of bioreductive agents, such as nitroindoles and nitroquinolines, for cancer treatment.