3 research outputs found
7-Ethynylcoumarins: Selective Inhibitors of Human Cytochrome P450s 1A1 and 1A2
To discover new selective mechanism-based P450 inhibitors,
eight
7-ethynylcoumarin derivatives were prepared through a facile two-step
synthetic route. Cytochrome P450 activity assays indicated that introduction
of functional groups in the backbone of coumarin could enhance the
inhibition activities toward P450s 1A1 and 1A2, providing good selectivity
against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin
(7ETMC) showed IC<sub>50</sub> values of 0.46 μM and 0.50 μM
for P450s 1A1 and 1A2 in the first six minutes, respectively, and
did not show any inhibition activity for P450s 2A6 and 2B1 even at
the dose of 50 μM. All of the inhibitors except 7-ethynyl-3-methyl-4-phenylcoumarin
(7E3M4PC) showed mechanism-based inhibition of P450s 1A1 and 1A2.
In order to explain this mechanistic difference in inhibitory activities,
X-ray crystallography data were used to study the difference in conformation
between 7E3M4PC and the other compounds studied. Docking simulations
indicated that the binding orientations and affinities resulted in
different behaviors of the inhibitors on P450 1A2. Specifically, 7E3M4PC
with its two-plane structure fits into the P450 1A2’s active
site cavity with an orientation leading to no reactive binding, causing
it to act as a competitive inhibitor
7-Ethynylcoumarins: Selective Inhibitors of Human Cytochrome P450s 1A1 and 1A2
To discover new selective mechanism-based P450 inhibitors,
eight
7-ethynylcoumarin derivatives were prepared through a facile two-step
synthetic route. Cytochrome P450 activity assays indicated that introduction
of functional groups in the backbone of coumarin could enhance the
inhibition activities toward P450s 1A1 and 1A2, providing good selectivity
against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin
(7ETMC) showed IC<sub>50</sub> values of 0.46 μM and 0.50 μM
for P450s 1A1 and 1A2 in the first six minutes, respectively, and
did not show any inhibition activity for P450s 2A6 and 2B1 even at
the dose of 50 μM. All of the inhibitors except 7-ethynyl-3-methyl-4-phenylcoumarin
(7E3M4PC) showed mechanism-based inhibition of P450s 1A1 and 1A2.
In order to explain this mechanistic difference in inhibitory activities,
X-ray crystallography data were used to study the difference in conformation
between 7E3M4PC and the other compounds studied. Docking simulations
indicated that the binding orientations and affinities resulted in
different behaviors of the inhibitors on P450 1A2. Specifically, 7E3M4PC
with its two-plane structure fits into the P450 1A2’s active
site cavity with an orientation leading to no reactive binding, causing
it to act as a competitive inhibitor
Discovery of a Series of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion
Effective inhibitors of cancer cell migration and invasion
can
potentially lead to clinical applications as a therapy to block tumor
metastasis, the primary cause of death in cancer patients. To this
end, we have designed and synthesized a series of thiazole derivatives
that showed potent efficacy against cell migration and invasion in
metastatic cancer cells. The most effective compound, <b>5k</b>, was found to have an IC<sub>50</sub> value of 176 nM in the dose-dependent
transwell migration assays in MDA-MB-231cells. At a dose of 10 μM, <b>5k</b> also blocked about 80% of migration in HeLa and A549 cells
and 60% of invasion of MDA-MB-231 cells. Importantly, the majority
of the derivatives exhibited no apparent cytotoxicity in the clonogenic
assays. The low to negligible inhibition of cell proliferation is
a desirable property of these antimigration derivatives because they
hold promise of low toxicity to healthy cells as potential therapeutic
agents. Mechanistic studies analyzing the actin cytoskeleton by microscopy
demonstrate that compound <b>5k</b> substantially reduced cellular
f-actin and prevented localization of fascin to actin-rich membrane
protrusions. These results suggest that the antimigration activity
may result from impaired actin structures in protrusions that are
necessary to drive migration