title: Pre-mRNA splicing-modulatory pharmacophores: the total synthesis of herboxidiene, a pladienolide-herboxidiene hybrid analog and related derivatives.
abstract: Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels-Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC50s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas PI, MS 1000, Memphis, Tennessee 38105, United States.
authors.forename: Chandraiah
authors.initials: C
authors.lastname: Lagisetti
authors.forename: Maria V
authors.initials: MV
authors.lastname: Yermolina
authors.forename: Lalit Kumar
authors.initials: LK
authors.lastname: Sharma
authors.forename: Gustavo
authors.initials: G
authors.lastname: Palacios
authors.forename: Brett J
authors.initials: BJ
authors.lastname: Prigaro
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
mesh_terms: D017398:Alternative Splicing; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D061565:Cycloaddition Reaction; D015195:Drug Design; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005233:Fatty Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012322:RNA Precursors / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D005233:Fatty Alcohols; D018942:Macrolides; D011714:Pyrans; D012322:RNA Precursors; C522342:pladienolide B; C076087:herboxidiene; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2