# Development of Glycoconjugated MAGL Inhibitors with Glucose-Dependent Antiproliferative Activity

## TL;DR

Researchers developed new MAGL inhibitors that work better in low-glucose conditions, potentially targeting cancer cells more effectively.

## Contribution

First-in-class glycoconjugated MAGL inhibitors with glucose-dependent antiproliferative activity in cancer cells.

## Key findings

- Glycoconjugates 17 and 18 inhibited human MAGL with IC50 values of 43.3 and 68.8 μM.
- Both compounds showed antiproliferative activity in low-glucose conditions but were inactive in high-glucose medium.
- The glucose-dependent activity suggests uptake/competition mechanisms in pancreatic cancer cells.

## Abstract

Monoacylglycerol lipase (MAGL) is a key regulator of lipid signaling networks implicated in tumor progression and represents an attractive anticancer target. To combine MAGL inhibition with potentially enhanced uptake by highly glycolytic cancer cells, we designed glycoconjugated analogs of a N-benzoylpiperidine MAGL inhibitor scaffold bearing a glucopyranose unit. An alkyne-functionalized benzoylpiperidine intermediate was prepared and coupled to azido sugars through a CuAAC “click” reaction to afford two triazole-linked glycoconjugates. In a colorimetric assay on human MAGL, the new compounds 17 and 18 inhibited the enzyme with IC50 values of 43.3 and 68.8 μM, respectively, confirming compatibility with MAGL inhibition albeit with reduced potency versus reference triazole-substituted benzoylpiperidine 13 (IC50 = 4.1 μM). In PANC-1 pancreatic cancer cells, both glycoconjugates were inactive in high-glucose medium, but displayed antiproliferative activity under low-glucose conditions (GI50 17 = 129 μM; GI50 18 = 12 μM), consistent with glucose-dependent uptake/competition. Overall, these first-in-class MAGL-targeting glycoconjugates provide a starting point for optimizing dual MAGL inhibition and metabolically driven cellular selectivity.