Síntese de ésteres derivados do ácido cinâmico, p-metoxicinâmico e ferúlico e avaliação da citotoxidade

Abstract

Cinnamic, p-methoxycinnamic and ferulic acids and their derivatives present a remarkable variety of biological activities reported in the literature, and are often studied as a structural model in the search for the development of highly effective new drugs. Therefore, this work aims to synthesize and evaluate the cytotoxic activity of esters derived from cinnamic acids (CA), pmethoxycinnamic (MA) and ferulic (FA) acids, against four human tumor cell lines SNB-19 (Astrocytoma), HCT-116 (Colon carcinoma - human), PC3 (Prostate), HL60 (Promyelocytic leukemia), in addition to a healthy L929 cell (murine fibroblast), aiming to establish a relationship-structure activity. Thus, eighteen new esters were synthesized by esterification of Stiglich. It is worth mentioning that eight derivatives were obtained from cinnamic acid (CA): 2,3-dihydro-1H-inden-5-yl cinnamate (CA-1), 1-oxo-1H-isochromen-6-yl cinnamate (CA-2), (S)-(4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl cinnamate (CA-3), 3-methoxyphenyl cinnamate (CA-4), 2-isopropyl-5-methylphenyl cinnamate (CA-5), 5-isopropyl-2-methylphenyl cinnamate (CA-6), 2-ethyl-4-formylphenyl cinnamate (CA-7) and rac-(2R, 5R)-2-methyl-5- (prop-1-en-2-yl)cyclohexyl cinnamate (CA-8). In addition, from the p-methoxykinnamic acid (MA) the derivatives were obtained: 2,3-dihydro-1H-inden-5-yl (E)-3-(4- methoxyphenyl)acrylate (MA-1), 1-oxo-1H-isochromen-6-yl (E)-3-(4-methoxyphenyl) acrylate (MA-2), (S)-(4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl (E)-3-(4-methoxyphenyl) acrylate (MA-3), 3-methoxybenzyl (E)-3-(4-methoxyphenyl)acrylate (MA-4), 2-isopropyl-5- methylphenyl (E)-3-(4-methoxyphenyl)acrylate (MA-5), 5-isopropyl-2-methylphenyl (E)-3-(4- methoxyphenyl)acrylate (MA-6) , 4-formyl-2-methoxyphenyl (E)-3-(4-methoxyphenyl)acrylate (MA-7) and rac-(2R, 5R)-2-(methyl-5-(prop-1-en-2-yl) cyclohexyl (E)-3-(4- methoxyphenyl)acrylate (MA-8). From the ferulic acid (FA), derivatives were obtained: 5- isopropyl-2-methylphenyl (E)-3-(3-hydroxy-4-methoxyphenyl)acrylate (FA-1a) and (E)-3-(3- hydroxy-4-methoxyphenyl) 2-isopropyl-5-methylphenyl (FA-1b). All compounds being new in the literature. The structures of these substances were characterized by spectroscopic (IR, 1H NMR and 13C NMR) and spectrometric (MS) methods. The cytotoxicity of the eighteen compounds was evaluated using the MTT colorimetric assay. The results of the tests showed that the compound 3-methoxybenzyl (E)-3-(4-methoxyphenyl)acrylate (MA-4) is the most potent against HCT-116, PC3 and SBN-19 cells, with the lowest IC50 = 16.2 μM in the HCT-116 strain. The compound (E)-3-(3-hydroxy-4-methoxyphenyl)acrylate 2-isopropyl-5-methylphenyl (FA1b) also showed moderate cytotoxicity in the HCT-116 strain (IC50 = 15.38 μM). In the HL60 strain, the 2-isopropyl-5-methylphenyl cinnamate compound (CA-5) was the only one that showed the highest cytotoxicity (IC50 = 25.2 μM). Both compounds showed selectivity towards normal cells (L929), indicating that the derivatives tested are good candidates for the study as new antineoplastic drugs.