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Structural Requirements for the Antiproliferative Activity of Pre‐mRNA Splicing Inhibitor FR901464
Author(s) -
Osman Sami,
Albert Brian J.,
Wang Yanping,
Li Miaosheng,
Czaicki Nancy L.,
Koide Kazunori
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201002402
Subject(s) - rna splicing , messenger rna , precursor mrna , alternative splicing , computational biology , microbiology and biotechnology , chemistry , biology , rna , gene , biochemistry
FR901464, a natural product isolated from a bacterium source, activates a reporter gene, inhibits pre‐mRNA splicing, and shows antitumor activity. We previously reported the development of a more potent analogue, meayamycin, through the total synthesis of FR901464. Herein, we report detailed structure–activity relationships of FR901464 that revealed the significance of the epoxide, carbon atoms in the tetrahydropyran ring, the Z geometry of the side chain, the 1,3‐diene moiety, the C4‐hydroxy group, and the C2′′‐carbonyl group. Importantly, the methyl group of the acetyl substituent was found to be inessential, leading to a new potent analogue. Additionally, partially based on in vivo data, we synthesized and evaluated potentially more metabolically stable analogues for their antiproliferative activity. These structural insights into FR901464 may contribute to the simplification of the natural product for further drug development.