Date

Thursday 25 Sep 2025

Time

15:15 - 15:45

Location

BW029

Supervisor

Mario van der Stelt

2nd reviewer

Jeroen Codee

Jury

Bobby Florea

The endocannabinoid system regulates cognitive and physiological processes in the central nervous systems (CNS) via lipid messengers called endocannabinoids (eCBs) 2-arachidonoylglycerol (2-AG) and anandamide (AEA). While their biosynthesis, function, and metabolism are well-characterised, their mode of transport remains unclear. Previously, a cyclopropene variant of arachidonic acid AA (.-2 cpAA) was synthesised. This analogue was selectively labelled in U-87 multiforme glioblastoma (U-87 MG) cells with a tetrazine fluorophore using inverse electron demand Diels-Alder (IEDDA) chemistry. To test how the cyclorpropene position affects the biological properties of these types of eCBs analogues, we designed and synthesised .-6 cyclopropene analogues of AA and AEA. The .-6 cyclopropene analogue of AA (.-6 cpAA) was succesfully synthesised using three consecutive Wittig reactions with homologating agents phosphonium salt 1 (PS1) and phosphonium salt 2 (PS2). However, subsequent attempts to obtain the .-6 cyclopropene analogue of AEA (.-6 cpAEA) through peptide coupling with cabonyldiimidazole (CDI) showed clear degradation of the .-6 cpAA, suggesting that the cyclopropene moiety may be sensitive to this carboxylic acid activating agent. Finally, to increase spatiotemporal control of .-6 cpAEA and AEA, photocaged derivatives were designed and partially synthesised. Together, this work establishes a foundation for using bio-orthogonal cyclopropene analogues as tools to investigate endocannabinoid signalling.