Synthesis of Ceramide PR280 Analogues Bearing Basic N-Acyl Modifications for Targeted Des1 Inhibition

Identifier:  TFG:10063

Handle: https://hdl.handle.net/20.500.11797/TFG10063

Authors:  Jiménez Jerez, Adrián

Abstract:
Dihydroceramide desaturase 1 (Des1) is a key enzyme in sphingolipid biosynthesis and a promising anticancer target. Its inhibition leads to dihydroceramide accumulation, promoting autophagy, while preventing the formation of ceramide and its pro-tumor metabolite sphingosine-1-phosphate. The SINTCARB group previously identified PR280 as a potent Des1 inhibitor incorporating a cyclopropenone moiety. This project focused on synthesizing three N-acylated PR280 analogues with basic functional groups, selected via docking studies. Their multi-step synthesis involved scaffold protection, stereoselective addition, global deprotection, and N-acylation. PR280-1, PR280-3, and PR280-7 were fully characterized, with isolated yields of 26%, 33%, and 13%, respectively.