fr-901464 and Neoplasms

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

Topics: Amides; Animals; Epoxy Compounds; Humans; Mice; Neoplasms; Phosphoproteins; RNA Splicing; RNA-Binding Proteins; Trans-Activators

We report the design and highly enantioselective synthesis of a potent analogue of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogues. We present results on the in vitro activity for this compound against several tumor cell lines.

Topics: Animals; Antineoplastic Agents; Biological Factors; Cell Line, Tumor; Cell Proliferation; Chlorocebus aethiops; COS Cells; Drug Design; Drug Screening Assays, Antitumor; Epoxy Compounds; Humans; Macrolides; Mice; Models, Molecular; Molecular Conformation; Neoplasms; NIH 3T3 Cells; Pyrans; Spiro Compounds; Stereoisomerism