Structure of compounds 1–7.

<p>Structure of compounds 1–7.</p

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 C₉‑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 C₉-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