A Stereoselective Synthesis of Lentiginosine

A concise stereoselective synthesis of (−)-lentiginosine, an iminosugar endowed with an interesting proapoptotic activity, has been accomplished using an enantiopure pyrroline <i>N</i>-oxide building block derived from d-tartaric acid. Key steps are a totally diastereoselective nucleophilic addition to the cyclic nitrone followed by a combination of two simultaneous and two tandem reactions occurring under the same conditions in a single laboratory operation. Natural (+)-lentiginosine can be synthesized by the same method but starting from l-tartaric acid

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

Structure of compounds 1–7.

<p>Structure of compounds 1–7.</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

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

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