title: Structural requirements for the antiproliferative activity of pre-mRNA splicing inhibitor FR901464.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Osman
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Albert
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Miaosheng
authors.initials: M
authors.lastname: Li
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Czaicki
authors.forename: Kazunori
authors.initials: K
authors.lastname: Koide
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004852:Epoxy Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology*; D012322:RNA Precursors / Q000187:drug effects*; D012326:RNA Splicing / Q000187:drug effects*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D004852:Epoxy Compounds; C104486:FR 901464; D011714:Pyrans; D012322:RNA Precursors; D013141:Spiro Compounds; C546442:meayamycin