Enantioselective Synthesis of a Cyclopropane Derivative of Spliceostatin A and Evaluation of Bioactivity

Abstract

Spliceostatin A is a potent inhibitor of spliceosomes and exhibits excellent anticancer activity against multiple human cancer cell lines. We describe here the design and synthesis of a stable cyclopropane derivative of spliceostatin A. The synthesis involved a cross-metathesis or a Suzuki cross-coupling reaction as the key step. The functionalized epoxy alcohol ring was constructed from commercially available optically active tri- O-acetyl-d-glucal. The biological properties of the cyclopropyl derivative revealed that it is active in human cells and inhibits splicing in vitro comparable to spliceostatin A.

Figure 1

Structures of spliceosome inhibitors 1–5

Figure 2

Impact of compound 5 on in vitro splicing. Average splicing efficiency relative to inhibitor concentration normalized to no-drug control. Compound 5; SSA, spliceostatin A.

Figure 3

Changes in nuclear speckle morphology. Fluorescent images of in HeLa cells nuclei incubated four hours with the indicated compound, then fixed and stained with DAPI (blue) and anti-SRSF2 antibody (magenta).

Scheme 1

Retrosynthesis of spliceostatin derivative

Scheme 2

Synthesis of dihydropyranone 18

Scheme 3

Synthesis of epoxy alcohol derivatives

Scheme 4

The synthesis of spliceostatin derivative 5