Síntese, caracterização e avaliação da atividade antineoplásica de novas 3-(aminometil)naftoquinonas e de seus complexos de platina

• Ano de defesa: 2011
• Autor(a) principal: Silva, Gustavo Bezerra da
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Programa de Pós-graduação em Química; Química
• Palavras-chave em Português: Naftoquinona; Derivado de naftoquinona; Complexo metálico; Síntese inorgânica; Naphthoquinone; Naphthoquinone derivative; Metal complex; Inorganic synthesis; CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA
• Link de acesso: https://app.uff.br/riuff/handle/1/20724

main objectives of this work were the design and synthesis of novel platinum complexes with antineoplastic activity higher than cisplatin. Considering that 3-aminomethyl- 2-hydroxy-1,4-naphthoquinones exhibit anticancer activity, novel compounds of this class containing additional nitrogen groups have been designed for complexation with Pt2+ and Pt4+ cations. Three series of Mannich bases (MB) derived from lawsone, 3-(R1-amino-R2-methyl- 2-hydroxy-1,4-naphthoquinone (R1 = 3-chloropropyl, 3.11-3.19, 2-ethylcarbamate, 3.21-3.26, e 3-propylcarbamate, 3.28-3.33) have been synthesized. Chloro-substitution for ammines in compounds 3.11-3.19 has not yet been achieved. The conditions for carbamate deprotection in MB 3.21-3.33 still have to be improved. The electrochemical behavior of the novel MB has been studied in DMSO. Two naphthoquinone redox processes and one redox process of autoprotonated species were observed. The nature of the R2 substituent was found to influence the first reduction potential, which decreases in the following order: 4-NO2-C6H4 ~ 2,4-2Cl-C6H3 > 4-Br-C6H4 > 2-pyridil > 2-OH-C6H4 ~ C6H5 ~ 5-Br-2-OH-C6H3 > 3-OH-C6H4 > H. R1, however, has little influence on the electrochemical potentials. The MB in vitro tumoricidal activity was evaluated against human tumor cells (melanoma), HCT-8 (colon), SF-295 (brain) e HL-60(leukaemia). The MB with R2 = 2-OHC6H4 and 5-Br-2-OH-C6H3 were the most active. 3.14 (R1 = 3 cloropropil e R2 = 2-OH-C6H4) was the most active for leukaemia (IC50 = 7.8 mM), and 3.22 (R1 = 2-ethylcarbamate and R2 = 2-OH-C6H4), for colon, brain and melanoma (IC50 = 9.5, 16.4 and 28.4 mM, respectively). An analysis of the IC50 values obtained for these and a number of other MB has evidenced the difficulty in finding a correlation between structure and activity, most probably because cytotoxicity may be caused by several mechanisms of action. In addition, no correlation between cytotoxicity and electrochemical potentials has been found. The Pt4+ complexes of 3-(R1-amino(pyridin-2-yl)methyl)-2 hydroxy-1,4-naphthoquinones (R1 = n-butyl 5.11, n-heptyl 5.12, e n-decyl 5.13), cis,trans [Pt(5.11-5.13)Cl2(OH)2] (5.17-5.19) have been synthesized by oxidation of the platinum(II) complexes [Pt(5.11- 5.13)Cl2] (5.14-5.16). The cyclic voltammograms (in CH3CN+0.1 n-Bu4NClO4) have shown the Pt4+/Pt2+ reduction and a deprotonated naphthoquinone redox process, due to the dissociation of hydroxyl ligands, upon Pt4+ reduction. The IC50 values obtained for the Pt4+ complexes were encouraging, in spite of the fact that, except for the melanoma cell line, they were less active than the free MB. All complexes were more active than cisplatin and the Pt2+ analogues, 5.19 (R1 = n-decyl) being twice as active against leukaemia (IC50 = 6.0 mM) than the Pt2+ analogue 5.16. This value is close to that obtained for the free MB 5.13 (IC50 = 3.8 mM). In general the Pt4+ complexes with R1 = ndecyl were the most active.