Synthesis, characterization and biological activities of mononuclear Co(III) complexes as potential bioreductively activated prodrugs.
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.
Souza
Elizabeth Teixeira
ET
Departamento de Química Inorgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, 21945-970 Rio de Janeiro, RJ, Brazil.
Castro
Lidiane Cavalcante
LC
Castro
Frederico Augusto Vieira
FA
do Canto Visentin
Lorenzo
L
Pinheiro
Carlos Basílio
CB
Pereira
Marcos Dias
MD
de Paula Machado
Sérgio
S
Scarpellini
Marciela
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003035:Cobalt / Q000737:chemistry / Q000494:pharmacology*; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000254:growth & development*
D000970:Antineoplastic Agents; D006573:Heterocyclic Compounds, 1-Ring; D011355:Prodrugs; D003035:Cobalt