Planejamento, síntese e avaliação da atividade citotóxica de benzamidinas e arilguanidinas derivadas de carboidratos

Abstract

Benzamidines and arylguanidines derivatives exhibit interesting antitumor activity from its intercalation with the DNA molecule. This may occur by ð-stacking interactions between aromatic rings of ligands and the bases cytosine and guanine, as well as by electrostatic interactions between guanidino and amidino groups (which may be protonated in biological systems because they are strongly basic) with phosphate groups of DNA. On the other hand, antitumor drugs containing some type of carbohydrate in their structure are described in the literature. The presence of saccharide units in the structures of these drugs is critical to its antineoplastic activity, either by providing a better interaction with their respective target, or by improving the physicochemical properties of the drug, due to the polarity shown by carbohydrates. In this work benzamidines and arylguanidines derived from carbohydrates were synthesized for evaluation of their potential as candidates for new antitumor drugs. The synthesis of benzamidines (11-18) was carried out by the reaction between 3,4-diaminobenzamidines (4 and 6) with 4-hydroxy-3-methoxybenzaldehyde glycosides (7-10) in the presence of p-benzoquinone. The deacetylation of peracetylated benzamidines 11-18 allowed obtaining the benzamidines derivatives 19-26. The synthesis of arylguanidines was performed from the initial reaction of glycosides 7-10 with o-phenylenediamine in the presence of p-benzoquinone, which lead to obtaining the nitrobenzimidazoles derivatives 27-30. The catalytic hydrogenation of the nitrocompounds obtained yielded the amines 31-34, which by reaction with N,N'-bis-(tert-butoxycarbonyl)-N''-(trifluoromethanesulfonyl)guanidine or N,N-di-(tert-butoxycarbonyl)thiourea and 2-chloro-N-methylpyridine were converted to peracetylated arylguanidines derivatives 37-40. The reaction of 37-40 with trifluoroacetic acid in dichloromethane allowed the obtention of peracetylated guanidines 43-46, which after deacetylation reaction, provided the final guanidines of interest 47-50. Neither of benzamidines evaluated showed high cytotoxic potential against the tested tumor cell lines (HCT116: colon cancer, OVCAR-8: ovarian cancer, SF-295: human glioblastoma), although derivatives 14, 16, 17, 18, 20 and 21 have shown some specific inhibition against SF-295 cells at 25 mg/mL.