2. Academic Validation
  3. Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A

Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A

  • Bioorg Med Chem Lett. 2019 Sep 15;29(18):2681-2685. doi: 10.1016/j.bmcl.2019.07.023.
Jean-Baptiste Garsi 1,  Vito Vece 1,  Lorenzo Sernissi 1,  Catherine Auger-Morin 1,  Stephen Hanessian 2,  Alison N McCracken 3,  Elizabeth Selwan 3,  Cuauhtemoc Ramirez 3,  Amogha Dahal 3,  Nadine Ben Romdhane 3,  Brendan T Finicle 3,  Aimee L Edinger 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, QC H3C 3J7, Canada.
  • 2 Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, QC H3C 3J7, Canada. Electronic address: stephen.hanessian@umontreal.ca.
  • 3 Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA.
  • 4 Department of Developmental and Cell Biology, University of California, Irvine, 2128 Natural Sciences 1, CA 92697-2300, USA. Electronic address: aedinger@uci.edu.
PMID: 31383588 DOI: 10.1016/j.bmcl.2019.07.023
Abstract

Inspired by the cytotoxicity of perphenazine toward Cancer cells and its ability to activate the serine/threonine protein Phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.

Keywords

Cytotoxicity FL5.12; Hybrid structures; Nutrient transport down-regulation; Sphingolipid; Vacuolation.

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