What is the significance of the tetrahydropyran ring in FR901464 analogs?

Label:chem

Topic
FR901464's tetrahydropyran-spiroepoxide is crucial for its covalent binding to the spliceosome, and a tetrahydrofuran analog showed significantly reduced potency.
Answer
A study indicates the significance of the tetrahydropyran ring, as it is essential for presenting the epoxide towards the spliceosome, allowing for covalent binding to the PHF5A-SF3B1 complex. Analogs lacking the epoxide moiety were far less potent due to the absence of covalent binding. The tetrahydrofuran analog 1, despite containing the epoxide, may not position it correctly for covalent bond formation with the reactive cysteine in PHF5A.
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