Bioactivation of Fluorinated
2-Aryl-benzothiazole
Antitumor Molecules by Human Cytochrome P450s 1A1 and 2W1 and Deactivation
by Cytochrome P450 2S1
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Abstract
Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole
(5F 203)
and 5-fluoro-2-(3,4-dimethoxyphenyl)-benzothiazole (GW 610) contain
the benzothiazole pharmacophore and possess potent and selective in
vitro antitumor properties. Prior studies suggested the involvement
of cytochrome P450 (P450) 1A1 and 2W1-mediated bioactivation in the
antitumor activities and P450 2S1-mediated deactivation of 5F 203
and GW 610. In the present study, the biotransformation pathways of
5F 203 and GW 610 by P450s 1A1, 2W1, and 2S1 were investigated, and
the catalytic parameters of P450 1A1- and 2W1-catalyzed oxidation
were determined in steady-state kinetic studies. The oxidations of
5F 203 catalyzed by P450s 1A1 and 2W1 yielded different products,
and the formation of a hydroxylamine was observed for the first time
in the latter process. Liquid chromatography–mass spectrometry
(LC-MS) analysis with the synthetic hydroxylamine and also a P450
2W1/5F 203 incubation mixture indicated the formation of dGuo adduct
via a putative nitrenium intermediate. P450 2W1-catalyzed oxidation
of GW 610 was 5-fold more efficient than the P450 1A1-catalyzed reaction.
GW 610 underwent a two-step oxidation process catalyzed by P450 1A1
or 2W1: a regiospecific <i>O</i>-demethylation and a further
hydroxylation. Glutathione (GSH) conjugates of 5F 203 and GW 610,
presumably through a quninoneimine and a 1,2-quinone intermediate,
respectively, were detected. These results demonstrate that human
P450s 1A1 and 2W1 mediate 5F 203 and GW 610 bioactivation to reactive
intermediates and lead to GSH conjugates and a dGuo adduct, which
may account for the antitumor activities of 5F 203 and GW 610 and
also be involved in cell toxicity. P450 2S1 can catalyze the reduction
of the hydroxylamine to the amine 5F 203 under anaerobic conditions
and, to a lesser extent, under aerobic conditions, thus attenuating
the anticancer activity
