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Synthesis, characterization and biological activities of mononuclear Co(III) complexes as potential bioreductively activated prodrugs.

Abstract：

:Aiming to investigate the use of tridentate ligands to develop new bireductively activated prodrugs, two N(2)O-donor ligands (HL1: [(2-hydroxybenzyl)(2-(imidazol-2-yl)ethyl)]amine; and HL2: [(2-hydroxybenzyl)(2-(pyridil-2-yl)ethyl]amine) were used to synthesize new Co(III) complexes, 1 and 2. Both complexes were characterized by X-ray crystallography, mass spectrometry, electrochemistry, IR, UV-visible and (1)H NMR spectroscopies. Electrochemical data in methanol revealed that the Co(III)-->Co(II) reduction of 1 (-0.84V vs. normal hydrogen electrode - NHE) is more positive than 2 (-1.13V vs. NHE), while it was expected to be more negative due to better sigma-donor ability of imidazole ring in HL1, compared to pyridine in HL2. Considering that reduction processes on Co(III) center may involve the lowest unoccupied molecular orbital (LUMO), it might play an important role on the electronic properties of the complexes, and could explain the observed redox potentials. Then, geometry optimizations of 1 and 2 were performed using the density functional theory (DFT), and different group participation in their LUMO is demonstrated. Using Saccharomyces cerevisiae cells as eukaryotic model, it is shown that in situ generated reduced species, 1(red) and 2(red), have high capacity to inhibit cellular growth, with IC50 (0.50mM for both complexes) lower than cisplatin IC50 (0.6mM) at the same time of exposure. Regarding to their ability to promote S. cerevisiae cells death, after 24 h, cells became susceptible only when exposed to 1(red) and 2(red): (i) at concentrations higher than 0.5mM in a non-dose dependence, and (ii) in anaerobic metabolism. These data reveal the potential of 1 and 2 as bioreductively activated prodrugs, since their oxidized forms do not present expressive activities when compared to their reduced forms.

journal_name

J Inorg Biochem

journal_title

Journal of inorganic biochemistry

authors

Souza ET,Castro LC,Castro FA,do Canto Visentin L,Pinheiro CB,Pereira MD,de Paula Machado S,Scarpellini M

doi

10.1016/j.jinorgbio.2009.07.008

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

1355-65

issue

eissn

0162-0134

issn

1873-3344

pii

S0162-0134(09)00148-2

journal_volume

103

pub_type

杂志文章

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Synthesis, characterization and biological activities of mononuclear Co(III) complexes as potential bioreductively activated prodrugs.