title: Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue.
abstract: We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner-Wadsworth-Emmons (HWE) macrocyclization, and a new DSC-mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity.
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Michail
authors.initials: M
authors.lastname: Tsakos
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Lise L
authors.initials: LL
authors.lastname: Clement
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Eva S
authors.initials: ES
authors.lastname: Schaffert
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Frank N
authors.initials: FN
authors.lastname: Olsen
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Rupiani
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Djurhuus
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Wanwan
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Jacobsen
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
authors.forename: Nikolaj L
authors.initials: NL
authors.lastname: Villadsen
authors.affiliation: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark. thpou@chem.au.dk.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Poulsen
mesh_terms: D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D055666:Lipopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D047630:Depsipeptides
chemical_list: D055666:Lipopeptides; D010456:Peptides, Cyclic; C000723972:rakicidins; D047630:Depsipeptides
keywords: antitumor agents; cyclolipodepsipeptides; natural products; total synthesis; tumor hypoxia