Enantioselective synthesis of spliceostatin E and evaluation of biological activity

Abstract

An enantioselective total synthesis of spliceostatin E has been accomplished. The δ-lactone unit A was constructed from readily available (R)-glycidyl alcohol using a ring-closing olefin metathesis as the key reaction. A cross-metathesis of ring A containing δ-lactone and the functionalized tetrahydropyran B-ring provided spliceostatin E. Our biological evaluation of synthetic spliceostatin E revealed that it does not inhibit splicing in vitro and does not impact speckle morphology in cells. Spliceostatin E was reported to possess potent antitumor activity.

Figure 1

Structures of pladienolide B, FR901464, and spliceostatins A and E.

Scheme 1. Retrosynthesis of Spliceostatin E

Scheme 2. Synthesis of (S)-Dihydropyranone, 5

Scheme 3. Synthesis of Racemic Dihyropyranone

Scheme 4. Synthesis of Z-Alkene Acid 9

Scheme 5. Synthesis of Spliceostatin E

Figure 2

Impact of analogues on in vitro splicing. Average splicing efficiency vs inhibitor concentration normalized to DMSO control. SSE, spliceostatin E; SSA, spliceostatin A.

Figure 3

Changes in nuclear speckle morphology. SFRS2 (SC35) immunofluorescence in HeLa cells nuclei treated with (A) DMSO, (B) 1 μM pladienolide B, and (C) 0.1, 1, and 10 μM spliceostatin E, left to right.