Síntese, caracterização e estudo da atividade antitumoral e antibacteriana de alguns complexos metálicos de bismuto(III) e gálio(III)

Abstract

The most important application of metal complexes in clinicai medicine is the treatment of câncer. However, there are problems associated with their use, especially side effects and the emergence of resistance, which has not yet been solved. Similarly, the emergence of multi-resistant bactéria poses a serious public health concern. Therefore, increasing resistance to available drugs creates a demand for new chemotherapeutic agents. Aiming to combine the pharmacological properties of sulfasalazine (saz), sulfapyridine (sp), tetracycline (tc) and two tridentate heterocyclic ligands to the metal ions Bi (III) and Ga (III), this work describes the synthesis, physicochemical characterization both in solid state and in solution, the cytotoxic activity and antibacterial activity of seven novel metal complexes. The complexes [Bi(sp)3CI3], [Bi(saz)2CI], [Ga(saz)(H20)(0H)], [Bi(tc)(H20)CI2], [Ga(H20)2(tc)2](N03), [Bi(C2iH29N20)CI2] and [Bi(Ci3HnN2l20)CI2] were characterized by elemental analysis and conductimetric, mass spectrometry, IR and 1H NMR . The structures of the complexes [Bi(C2iH29N20)CI2] and [Bi(sp)3CI3] were also determined by single crystal X-ray diffraction methods. The coordination of bismuth to sulfapyridin occurred via the sulfonamidic nitrogen and improved the antibacterial effect as compared to the free ligand. The coordination of bismuto(lll) to sulfasalazine was bidentate through the oxygens of the carboxylate and the phenolic group and did not improve the activity in any of the bacterial strains tested. However, both complexes showed higher cytotoxic activity in tumor cells than their free ligands, with the IC5o for the compound Bi (III) and sulfasalazine equal to 9.7 mol L1. Gallium (III) also coordinated to sulfasalazine through two oxygens of the salicylate ring. The coordination of Ga (III) to sulfasalazine did not increase the antibacterial activity considerably, and its biological activity against tumor cells was relatively close to that of the ligand. Tetracycline coordinated to Bi (III) in a bidentate manner via the amide nitrogen and the hydroxyl oxygen at C3 after deprotonation. The complex [Bi(tc)(H20)CI2] appeared as a promising antibacterial agent, with an antibacterial activity similar to that of tetracycline in sensitive strains and able to overcome bacterial resistance in resistant strains of Escherichiacoli carrying the plasmid pBR322. Gallium (III) ions bind to two tetracycline molecules acting as bidentate ligand through the carbonyl oxygen of the amide and the oxygen of the deprotonated hydroxyl group at C3. The Ga (III) complex with tetracycline was also able to overcome bacterial resistance to the free antibiotic. These results are very promising since bacterial resistance is the major obstacle to the clinicai use of tetracyclines. The bismuth(lll) complex with tetracycline was 7 times more active than free tetracycline against tumor cells and that with gallium(lll) was 12.7 times more active. Finally, NN'0 donor ligands coordinated to the bismuth (III) in a tridentate manner to form similar structures of type [Bi(L)CI2]. Concerning the antitumoral potential of these compounds, it is worth noting that they are among the most active bismuth compounds described to date. IC5o values obtained for the complex [Bi(C2iH29N20)Cl2] and [Bi(Ci3Hn N2l20)CI2] were 0,3 e 0,4 pmol L1, respectively.