5 research outputs found
Pyranoflavones: A Group of Small-Molecule Probes for Exploring the Active Site Cavities of Cytochrome P450 Enzymes 1A1, 1A2, and 1B1
Selective inhibition of P450 enzymes
is the key to block the conversion of environmental procarcinogens
to their carcinogenic metabolites in both animals and humans. To discover
highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1,
as well as to investigate active site cavities of these enzymes, 14
novel flavone derivatives were prepared as chemical probes. Fluorimetric
enzyme inhibition assays were used to determine the inhibitory activities
of these probes toward P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly
selective P450 1B1 inhibitor 5-hydroxy-4′-propargyloxyflavone
(5H4′FPE) was discovered. Some tested compounds also showed
selectivity between P450s 1A1 and 1A2. α-Naphthoflavone-like
and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2,
while β-naphthoflavone-like flavone derivatives showed selective
inhibition of P450 1A1. On the basis of structural analysis, the active
site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating
a planar long strip cavity and a planar triangular cavity, respectively
Rational Design of a Boron-Modified Triphenylethylene (GLL398) as an Oral Selective Estrogen Receptor Downregulator
Development
of orally bioavailable nonsteroidal selective estrogen
receptor downregulators (SERDs) provides clinical opportunities for
the long-term treatment and adjuvant therapy of breast cancer at all
stages. We describe the design, synthesis, and identification of a
boron-modified GW7604 derivative (GLL398, <b>9</b>), a SERD
candidate, in which a boronic acid functional group replaces the phenolic
hydroxyl group of GW7604. Compound <b>9</b> strongly binds to
ERα in a fluorescence resonance energy transfer binding assay
(IC<sub>50</sub> = 1.14 nM) and potently degrades ERα in MCF-7
breast cancer cells (IC<sub>50</sub> = 0.21 μM). Most importantly,
the introduction of the boronic acid group confers superior oral bioavailability
of <b>9</b> (AUC = 36.9 μg·h/mL) in rats as compared
to GW7604 (AUC = 3.35 μg·h/mL). The strikingly favorable
pharmacokinetic property of <b>9</b> makes it a promising oral
SERD suitable for clinical evaluation
Fulvestrant‑3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD)
Orally bioavailable SERDs may offer
greater systemic drug exposure,
improved clinical efficacy, and more durable treatment outcome for
patients with ER-positive endocrine-resistant breast cancer. We report
the design and synthesis of a boronic acid modified fulvestrant (<b>5</b>, ZB716), which binds to ERα competitively (IC<sub>50</sub> = 4.1 nM) and effectively downregulates ERα in both
tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore,
It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in
mice, indicating its promising clinical utility as an oral SERD
A Ligand-Based Drug Design. Discovery of 4‑Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2
In
humans, cytochrome P450 1A2 is the major enzyme metabolizing
environmental arylamines or heterocyclic amines into carcinogens.
Since evidence shows that planar triangle-shaped molecules are capable
of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin
derivatives were designed and synthesized for these studies. Among
these compounds, 7,8-furanoflavone time-dependently inhibits P450
1A2 with a <i>K</i><sub>I</sub> value of 0.44 μM.
With a 5 min preincubation in the presence of NADPH, 0.01 μM
7,8-furanoflavone completely inactivates P450 1A2 but does not influence
the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin,
is found to be a competitive inhibitor, showing high selectivity for
the inhibition of P450 1A2 with a <i>K</i><sub>i</sub> of
0.39 μM, 155- and 52-fold lower than its <i>K</i><sub>i</sub> values against P450s 1A1 and 1B1, respectively. In yeast
AhR activation assays, 7,8-pyrano-4-trifluoromethylÂcoumarin
does not activate aryl hydrocarbon receptor when the concentration
is lower than 1 μM, suggesting that this compound would not
up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition
assays show that 7,8-pyrano-4-trifluoromethylÂcoumarin decreases
the MROD activity in HepG2 cells at concentrations higher than 1 μM.
Thus, using 7,8-pyrano-4-trifluoromethylÂcoumarin, a selective
and specific P450 1A2 action suppression could be achieved, indicating
the potential for the development of P450 1A2-targeting cancer preventive
agents
A Ligand-Based Drug Design. Discovery of 4‑Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2
In
humans, cytochrome P450 1A2 is the major enzyme metabolizing
environmental arylamines or heterocyclic amines into carcinogens.
Since evidence shows that planar triangle-shaped molecules are capable
of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin
derivatives were designed and synthesized for these studies. Among
these compounds, 7,8-furanoflavone time-dependently inhibits P450
1A2 with a <i>K</i><sub>I</sub> value of 0.44 μM.
With a 5 min preincubation in the presence of NADPH, 0.01 μM
7,8-furanoflavone completely inactivates P450 1A2 but does not influence
the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin,
is found to be a competitive inhibitor, showing high selectivity for
the inhibition of P450 1A2 with a <i>K</i><sub>i</sub> of
0.39 μM, 155- and 52-fold lower than its <i>K</i><sub>i</sub> values against P450s 1A1 and 1B1, respectively. In yeast
AhR activation assays, 7,8-pyrano-4-trifluoromethylÂcoumarin
does not activate aryl hydrocarbon receptor when the concentration
is lower than 1 μM, suggesting that this compound would not
up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition
assays show that 7,8-pyrano-4-trifluoromethylÂcoumarin decreases
the MROD activity in HepG2 cells at concentrations higher than 1 μM.
Thus, using 7,8-pyrano-4-trifluoromethylÂcoumarin, a selective
and specific P450 1A2 action suppression could be achieved, indicating
the potential for the development of P450 1A2-targeting cancer preventive
agents