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
  • 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: [email protected].
  • 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: [email protected].
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.