Development of Glycoconjugated MAGL Inhibitors with Glucose-Dependent Antiproliferative Activity

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Biochemistry

Background:

• Monoacylglycerol lipase (MAGL) is crucial in lipid signaling and a target for cancer treatment.
• Highly glycolytic cancer cells may offer enhanced drug uptake.
• Glycoconjugation can improve drug targeting and cellular uptake.

Purpose of the Study:

• To design and synthesize novel MAGL inhibitors with enhanced cancer cell uptake.
• To evaluate the anticancer potential of glycoconjugated MAGL inhibitors.
• To investigate the role of glucose metabolism in the cellular activity of these compounds.

Main Methods:

• Synthesis of alkyne-functionalized benzoylpiperidine intermediates.
• CuAAC "click" reaction to couple intermediates with azido sugars, forming triazole-linked glycoconjugates.
• Enzyme inhibition assays (colorimetric) on human MAGL.
• Antiproliferative assays on PANC-1 pancreatic cancer cells under varying glucose conditions.

Main Results:

• Two novel triazole-linked glycoconjugates (compounds 17 and 18) were synthesized.
• Compounds 17 and 18 inhibited human MAGL with IC50 values of 43.3 μM and 68.8 μM, respectively.
• Glycoconjugates showed antiproliferative activity in PANC-1 cells only under low-glucose conditions (GI50 values of 129 μM and 12 μM), suggesting glucose-dependent uptake.

Conclusions:

• First-in-class MAGL-targeting glycoconjugates were developed.
• These compounds demonstrate potential for dual MAGL inhibition and metabolically driven cellular selectivity.
• Further optimization is warranted for developing effective MAGL-targeted anticancer therapies.