FR-901464

FR901464 is a cytotoxic natural product that binds splicing factor 3B subunit 1 (SF3B1) and PHD finger protein 5A (PHF5A), the components of the human spliceosome. The amide-containing tetrahydropyran ring binds SF3B1, and it remains unclear how the substituents on the ring contribute to the binding. Here, we synthesized meayamycin D, an analogue of FR901464, and three additional analogues to probe the conformation through methyl scanning. We discovered that the amide-containing tetrahydropyran ring assumes only one of the two possible chair conformations and that methylation of the nitrogen distorts the chair form, dramatically reducing cytotoxicity. Meayamycin D induced alternative splicing of MCL-1, showed strong synergism with venetoclax in drug-resistant lung cancer cells, and was cancer-specific over normal cells. Meayamycin D incorporates an alkyl ether and shows a long half-life in mouse plasma. The characteristics of meayamycin D may provide an approach to designing other bioactive L-shaped molecules.

FR901464 and thailanstatins are potent cytotoxic natural products that share an amine-containing tetrahydropyran ring. We previously reported the synthesis of the tetrahydropyran component. Here, we changed the protecting group for the amine from Boc to tosyl, improving yields and the time economy. A highlight of the revised synthetic scheme is the use of lithium, t-butanol, and ethylenediamine in THF (nontraditional Birch reduction conditions) for the N-detosylation.