8 research outputs found
Inhibition of the ATPase activity of Hsp90 by different concentration of compounds 1–4.
<p>Radicicol and 17-AAG were used as positive controls. Data are the mean of two independent experiments performed in triplicate and were analyzed by t test (Hsp90 vs Hsp90+ testing compound): *P<0.05, **P<0.005.</p
SPR analysis results.
<p>Sensorgrams obtained by injecting different concentrations (from 0.020 to 1 <i>µ</i>M) of <b>1</b> (A), <b>2</b> (B), <b>3</b> (C), <b>4</b> (D), <b>5</b> (E), <b>6</b> (F) <b>7</b> (G) and radiciol (H) on immobilized Hsp90.</p
Docking calculation results.
<p>Three dimensional models (A and B) of (+)-lentiginosine (1, yellow) and (−)-lentiginosine (2, green) with HSP90. The target molecule is depicted by sky blue ribbon and the crucial amino acids by cpk (by atom type: C, purple; O, red; N, dark blue, H, white).</p
Schematic representation of the results obtained from limited proteolysis experiments.
<p>The preferential cleavage sites detected on recombinant Hsp90, and on the Hsp90/<b>1</b> complex are in black. The Hsp90 N-terminal domain is highlighted in light grey, the middle domain is boxed and the C-terminal domain is highlighted in grey.</p
Aggregation kinetics of CS at 43°C determined by light scattering.
<p>The spontaneous aggregation of CS at 43<b>°</b>C (♦) and the aggregation of CS at 43<b>°</b>C in the presence of 0.075 µM Hsp90 (Δ) or of 0.075 µM Hsp90 and 0.3 µM compound <b>1</b> (▪), 0.3 µM compound <b>2</b> (•), 0.3 compound <b>3</b> (□), or 0.3 µM compound <b>4</b> (○) are shown.</p
A Chemical–Biological Study Reveals C<sub>9</sub>‑type Iridoids as Novel Heat Shock Protein 90 (Hsp90) Inhibitors
The potential of heat shock protein 90 (Hsp90) as a therapeutic
target for numerous diseases has made the identification and optimization
of novel Hsp90 inhibitors an emerging therapeutic strategy. A surface
plasmon resonance (SPR) approach was adopted to screen some iridoids
for their Hsp90 α binding capability. Twenty-four iridoid derivatives,
including 13 new natural compounds, were isolated from the leaves
of <i>Tabebuia argentea</i> and petioles of <i>Catalpa
bignonioides</i>. Their structures were elucidated by NMR, electrospray
ionization mass spectrometry, and chemical methods. By means of a
panel of chemical and biological approaches, four iridoids were demonstrated
to bind Hsp90 α. In particular, the dimeric iridoid argenteoside
A was shown to efficiently inhibit the chaperone in biochemical and
cellular assays. Our results disclose C<sub>9</sub>-type iridoids
as a novel class of Hsp90 inhibitors
ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors
A systematic study of medicinal chemistry
aimed at identifying
a new generation of HDAC inhibitors, through the introduction of a
thiol zinc-binding group (ZBG) and of an amide-lactam in the ω-position
of the polyethylene chain of the vorinostat scaffold, allowed the
selection of a new class of potent pan-HDAC inhibitors (pan-HDACis).
Simple, highly versatile, and efficient synthetic approaches were
used to synthesize a library of these new derivatives, which were
then submitted to a screening for HDAC inhibition as well as to a
preliminary in vitro assessment of their antiproliferative activity.
Molecular docking into HDAC crystal structures suggested a binding
mode for these thiol derivatives consistent with the stereoselectivity
observed upon insertion of amide-lactam substituents in the ω-position.
ST7612AA1 (<b>117</b>), selected as a drug candidate for further
development, showed an in vitro activity in the nanomolar range associated
with a remarkable in vivo antitumor activity, highly competitive with
the most potent HDAC inhibitors, currently under clinical trials.
A preliminary study of PK and metabolism is also illustrated