title: Effects of stereochemistry, saturation, and hydrocarbon chain length on the ability of synthetic constrained azacyclic sphingolipids to trigger nutrient transporter down-regulation, vacuolation, and cell death.
abstract: Constrained analogs containing a 2-hydroxymethylpyrrolidine core of the natural sphingolipids sphingosine, sphinganine, N,N-dimethylsphingosine and N-acetyl variants of sphingosine and sphinganine (C2-ceramide and dihydro-C2-ceramide) were synthesized and evaluated for their ability to down-regulate nutrient transporter proteins and trigger cytoplasmic vacuolation in mammalian cells. In cancer cells, the disruptions in intracellular trafficking produced by these sphingolipids lead to cancer cell death by starvation. Structure activity studies were conducted by varying the length of the hydrocarbon chain, the degree of unsaturation and the presence or absence of an aryl moiety on the appended chains, and stereochemistry at two stereogenic centers. In general, cytotoxicity was positively correlated with nutrient transporter down-regulation and vacuolation. This study was intended to identify structural and functional features in lead compounds that best contribute to potency, and to develop chemical biology tools that could be used to isolate the different protein targets responsible for nutrient transporter loss and cytoplasmic vacuolation. A molecule that produces maximal vacuolation and transporter loss is expected to have the maximal anti-cancer activity and would be a lead compound.
authors.affiliation: Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, QC H3C 3J7, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Perryman
authors.affiliation: Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, QC H3C 3J7, Canada.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Tessier
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Wiher
authors.affiliation: Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, QC H3C 3J7, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: O'Donoghue
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA.
authors.forename: Alison N
authors.initials: AN
authors.lastname: McCracken
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA.
authors.forename: Seong M
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Nguyen
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA.
authors.forename: Grigor S
authors.initials: GS
authors.lastname: Simitian
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA.
authors.forename: Matheus
authors.initials: M
authors.lastname: Viana
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rafelski
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA. Electronic address: aedinger@uci.edu.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Edinger
authors.affiliation: Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, QC H3C 3J7, Canada. Electronic address: stephen.hanessian@umontreal.ca.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D013107:Sphingolipids / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014617:Vacuoles / Q000187:drug effects*
chemical_list: D006838:Hydrocarbons; D026901:Membrane Transport Proteins; D013107:Sphingolipids
keywords: Azacycles; Ceramides; FTY720; Nutrient transporter loss; Sphingolipids