In search of constrained FTY720 and phytosphingosine analogs as dual acting anticancer agents targeting metabolic and epigenetic pathways

• Published in: European journal of medicinal chemistry Vol. 159; pp. 217 - 242
• Main Authors: Garsi, Jean-Baptiste, Sernissi, Lorenzo, Vece, Vito, Hanessian, Stephen, McCracken, Alison N., Simitian, Grigor, Edinger, Aimee L.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.11.2018; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chemistry, Medicinal; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epigenesis, Genetic - drug effects; Fingolimod Hydrochloride - analogs & derivatives; Fingolimod Hydrochloride - chemistry; Fingolimod Hydrochloride - pharmacology; Life Sciences & Biomedicine; Mice; Molecular Structure; Nutrient transporter; Pharmacology & Pharmacy; Protein phosphatase 2A; Ring-constrained sphingosines; Science & Technology; Sphingosine - analogs & derivatives; Sphingosine - chemical synthesis; Sphingosine - chemistry; Sphingosine - pharmacology; Structure-Activity Relationship; Vacuolation; Ring-constrained sphingosines; Cytotoxicity; Nutrient transporter; Vacuolation; Protein phosphatase 2A; DRUG; HISTONE DEACETYLASE INHIBITOR; DESIGN; DECOMPOSITION; MECHANISMS; VORINOSTAT; THERAPY; KINETICS; KILL CANCER-CELLS; EXPRESSION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.09.043

A series of compounds containing pyrrolidine and pyrrolizidine cores with appended hydrophobic substituents were prepared as constrained analogs of FTY720 and phytosphingosine. The effect of these compounds on the viability of cancer cells, on downregulation of the nutrient transport systems, and on their ability to cause vacuolation was studied. An attempt to inhibit HDACs with some phosphate esters of our analogs was thwarted by our failure to reproduce the reported inhibitory action of FTY720-phosphate. [Display omitted] •Evaluating effects of pyrrolizidines and pyrrolidines on nutrient restriction.•Probing functional group tolerance of the hydrophobic substituents.•Rationale and synthesis of constrained pyrrolidine phosphate esters as dual agents.