Theoretical studies of the tautomerism in 3-(2-R-Phenylhydrazono)-naphthalene- 1,2,4-triones: synthesis of copper(II) complexes and studies of antibacterial and antitumor activities

Abstract

Cálculos teóricos utilizando os funcionais B3LYP e PBE1PBE e as bases 6-31G(d) e 6-311+G(2d,p) para o sistema 3-(2-fenil-hidrazona)-naftaleno-1,2,4-triona, em solução (dmso) e em fase gasosa, evidenciaram, em ambos os casos, a maior estabilidade da forma ceto-hidrazona (rotâmeros Ia e Ib) comparada às formas enol-azo (rotâmeros IIa/IIb, por volta de 14 kcal mol -1 ) e III (aproximadamente 6 kcal mol -1 ). A natureza do substituinte no grupo fenil não influenciou a estabilidade relativa dos tautômeros. Estes resultados foram confirmados por dados espectroscópicos dos derivados HL1-HL13, sintetizados a partir da 2-hidroxi-1,4-naftoquinona e arilaminas (R = 4-OMe, 4-N 2 -C 6 H 5 , 4-Cl, 4-I, 3-I, 2-I, 4-COOH, 3-COOH, 4-CN, 3-CN, 4-NO 2 , 3-NO 2 , 2-NO 2 ). A avaliação da atividade anticâncer in vitro (contra linhagens de células cancerosas SF-295, HCT-8, MDAMB-435 e HL-60) e bactericida (Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia e Pseudomonas aeruginosa) dos compostos HL1-HL13 e dos seus respectivos complexos de cobre(II), 2 ], foi avaliada. Em geral a atividade bactericida foi baixa, exceto para o derivado HL5 (R = 3-I), mais ativo do que o controle; entretanto, seu complexo não foi ativo. Por outro lado, a complexação levou, em geral, ao aumento da atividade antitumoral dos pré-ligantes. O complexo [Cu(L13) 2 ] (R = 3-NO 2 ) apresentou moderada citotoxicidade contra leucemia humana (HL-60).DFT calculations using the B3LYP and PBE1PBE functionals with the standard 6-31G(d) and 6-311+G(2d,p) basis sets were carried out for the 3-(2-phenylhydrazone)-naphthalene-1,2,4-trione system in solution (dmso) and in the gas phase, and showed the keto-hydrazone forms (rotamers Ia and Ib) to be more stable than the enol-azo forms (rotamers IIa and IIb, by about 14 kcal mol ), independently of the nature of the substituent in the phenylene ring. These results were confirmed by spectroscopic data on the derivatives HL1-HL13, obtained from 2-hydroxy-1,4-naphthoquinone and arylamines (R = 4-OMe, 4-N 2 -C 6 H 5 , 4-Cl, 4-I, 3-I, 2-I, 4-COOH, 3-COOH, 4-CN, 3-CN, 4-NO 2 , 3-NO 2 , 2-NO 2 ). The in vitro antitumor (against SF-295, HCT-8, MDAMB-435 and HL-60 cancer cell lines) and antibacterial activities (Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa) of compounds HL1-HL13 and of their respective copper(II) complexes, ) 2 ], were tested. In general, these compounds exhibited low antibacterial activity, except for HL5 (R = 3-I), more active than the control; however, the corresponding complex was inactive. In contrast, increased cytotoxicity was observed upon complexation. Complex [Cu(L13) 2 ] (R = 3-NO 2 ) presented moderate cytotoxicity against human leukemia (HL-60).Keywords: naphthoquinones, copper(II) complexes, tautomerism, hydrazone compounds, antibacterial activity, antitumor activity Theoretical Studies of the Tautomerism in 3-(2-R-Phenylhydrazono)...

Advances in Copper Complexes as Anticancer Agents

“…The 1,2- and 1,4-naphthoquinone nuclei are commonly encountered in natural products, and their derivatives exhibit a wide range of pharmacological properties including anticancer activities. , Such properties are due to the interference of quinones in the electron transport chain by electron reduction processes, generating semiquinone radical (Q •– ) and hydroquinone anion (Q 2– ). , Incorporation of an azo group into 2-hydroxy-1,4-naphthoquinone has led to promising anticancer agents in which metal complexation with copper­(II) resulted in increased cytotoxicity . The relative stability of the tautomeric forms of 3-(2- R -phenylhydrazono)-naphthalene-1,2,4-trione derivatives (Figure ) is a function of the substituents …”

“…The results indicated that the presence of −NO 2 and −I groups were relevant for the antitumor activity. Formation of an organic free radical observed in the EPR spectrum of [Cu­( L 33o ) 2 ] might be responsible for the cytotoxic activity …”

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“…Nor-β-Lapachone ( 1 ) is a very important naphthoquinone since it has selective cytotoxicity to human lymphocytes, HL-60 leukemia cells and murine fibroblasts V79 [ 11 ]. This compound has been the basis for the synthesis of several important analogues or derivatives with improved biological activities [ 12 , 13 , 14 , 15 , 16 , 17 ]. Recently, it was demonstrated that the modification of the dihydrofuran ring of nor-β-lapachone ( 1 ) could considerably change its activity against cancer cells [ 18 , 19 , 20 , 21 ], Trypanosoma cruzi ( T. cruzi ) [ 22 , 23 , 24 , 25 , 26 ], and candidal agents [ 27 ].…”