SÍNTESE, CARACTERIZAÇÃO E AVALIAÇÃO DA CITOTOXICIDADE DE COMPLEXOS UTILIZANDO LANTÂNIO E OS LIGANTES BIOATIVOS CLORAMBUCIL, METOTREXATO E ÁCIDO ÚSNICO MODIFICADO

Abstract

According to Instituto Nacional do Cancer (INCA) the estimative for the period of 2020-2022 is 625,000 new cases per year, in 2020 259,000 deaths were caused by this disease, which represents 17.8% of the total number of deaths in Brazil. In this context, the development of new drugs that can be used in the treatment of these diseases has been the object of many research papers. In order to optimize this process, one of the strategies used in the production of new bioactive substances is the synthesis of metal complexes with organic ligands that have biological activity, aiming to enhance their effect. The organic compounds Chlorambucil, Methotrexate are substances that have anticancer biological activity and Usnic Acid (UA), in addition to anticâncer activity, also has antibacterial and antileishmania activity. UA, although widely studied for its bioactivity, is still not used like a drug due to its hepatotoxicity. Studies carried out with Ln3+ ions indicate that these material salso have anti-cancer properties. Thus, this work aims to synthesize complexes using Chlorambucil (La-CLA), Methotrexate (La-MTX) and Usnic Acid modified with Glycine (La-UAGly) as a ligand and Lanthanum as a metallic center, in order to enhance their biological activities. The compounds produced were characterized by infrared spectroscopy and 13C and 1H nuclear magnetic resonance, the results obtained indicate that coordination bond formed between the ligands and the La3+ occurred in a bidentate way through carboxylic group in all complexes. Elemental and thermogravimetric analyzes indicate that the stoichiometry obtained for Chlorambucil and modified usnic acid with glycine (UAGly) complexes were 2:1 ligand:metal and Methotrexate complex presented 3:2 ligand:metal ratio. The anticancer activity assays indicated that the La-CLA and La-MTX complexes showed better activity than the ligands against the cells line K562 (Chronic Myeloid Leukemia), HT-29 (Colorectal Cancer), Caco 2 (Human Colorectal Adenocarcinoma) and B16 -F10 (Murine Melanoma), with GI50 values in the range of 0.31-31.86µM for the first and 0.03-0.13µM for the second. The La-CLA complex showed selectivity index (SI) equal to 15.64 for the K562 cell line with respect to normal J774 cells (murine macrophages). The La-UAgly complex showed more activity than its precursor UAGly against the B16F10 and Caco-2 strains, with IS<1. The antileishmanial activity assay suggest that the complex formed between UAGly and La3+ has greater activity when compared to the UAGly, and antibacterial test indicate a loss of UA activity after modification with glycine, as well as for the La-UAGly complex.