Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A. Issue 18 (15th September 2019)

• Record Type: Journal Article
• Authors: Garsi, Jean-Baptiste; Vece, Vito; Sernissi, Lorenzo; Auger-Morin, Catherine; Hanessian, Stephen; McCracken, Alison N.; Selwan, Elizabeth; Ramirez, Cuauhtemoc; Dahal, Amogha; Romdhane, Nadine Ben; Finicle, Brendan T.; Edinger, Aimee L.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 18(2019)
• Page Start: 2681
• Page End: 2685
• Publication Date: 2019-09-15
• Subjects: Sphingolipid -- Nutrient transport down-regulation -- Cytotoxicity FL5.12 -- Hybrid structures -- Vacuolation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.07.023
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.