Syntheses of spliceostatins and thailanstatins: a review

Abstract

The spliceostatins/thailanstatins are a family of linear peptides/polyketides that inhibit pre-mRNA splicing, and as such act as potent cytotoxic compounds. These compounds generally contain 9 stereocenters spread over a common (2Z,4S)-4-acetoxy-2-butenamide fragment, an (all-cis)-2,3,5,6-tetrasubstituted tetrahydropyran fragment and a terminal oxane ring joined by a dienyl chain. Due to the impressive antitumor properties of these compounds, along with their complex structure, a number of total syntheses have been reported. This review will compare the synthetic strategies reported through the end of 2019.

Spliceostatins and Derivatives: Chemical Syntheses and Biological Properties of Potent Splicing Inhibitors

“…Current biochemical and structural studies are directed toward unraveling precise binding site and specific molecular interactions of these modulators with SF3B proteins. , A number of pharma and academic laboratories are working to bring derivatives of these compounds to clinical trials. , Furthermore, several spliceostatin derivatives have been designed for specific delivery of spliceostatin payloads using antibody–drug conjugates. ,, Since the isolation and discovery of the spliceostatin class of natural products, there has been immense interest in the total synthesis, structure–activity studies, exploration of novel structural derivatives, and development of spliceostatin natural product-based antisplicing drugs. Recently, Donaldson reported a short review on syntheses of spliceostatins and thailanstatins . The review focuses mainly on the synthesis, comparing route efficiency with respect to the number of steps, overall yield, and material cost of all synthetic methods through 2019 .…”

“…Recently, Donaldson reported a short review on syntheses of spliceostatins and thailanstatins. 36 The review focuses mainly on the synthesis, comparing route efficiency with respect to the number of steps, overall yield, and material cost of all synthetic methods through 2019. 36 In the present review, we outline past and present chemical syntheses showcasing strategies, new reactions, bioactivity of spliceostatin and thailanstatin natural products and their structural derivatives through 2020.…”

“…36 The review focuses mainly on the synthesis, comparing route efficiency with respect to the number of steps, overall yield, and material cost of all synthetic methods through 2019. 36 In the present review, we outline past and present chemical syntheses showcasing strategies, new reactions, bioactivity of spliceostatin and thailanstatin natural products and their structural derivatives through 2020. This review particularly emphasizes how chemical syntheses led to important structure activity relationship (SAR) studies, the design of structural derivatives, evaluation of their potent cytotoxic properties and other bioactivity.…”

Total Syntheses of Pladienolide-Derived Spliceosome Modulators

“…Most splicing modulators reported to date are naturally occurring molecules, including the FR class [ 12 , 13 , 14 , 15 ], herboxidiene class [ 16 , 17 ], and pladienolide class ( Figure 1 ). Among them, pladienolides are structurally unique in that they possess a highly substituted macrocyclic core structure that has captured the attention of the synthetic chemistry community.…”