Ergot alkaloid glycosides with immunomodulatory activities

Area of Science:

• Biochemistry
• Immunology
• Organic Chemistry

Background:

• Ergot alkaloids, such as elymoclavine and 9,10-dihydrolysergol (DH-lysergol), are known for their diverse biological activities.
• Glycosylation is a common strategy to modify the properties and activity of natural products.
• Understanding the immunomodulatory effects of modified ergot alkaloids can lead to novel therapeutic strategies.

Purpose of the Study:

• To synthesize novel glycosylated derivatives of elymoclavine and DH-lysergol using chemoenzymatic methods.
• To investigate the immunomodulatory activity of these new glycoconjugates on natural killer (NK) cell-mediated cytotoxicity.
• To compare the effects of elymoclavine and DH-lysergol glycosides on NK cell activity against different target cells.

Main Methods:

• Chemoenzymatic synthesis of beta-glucosides and lactosides from elymoclavine and DH-lysergol.
• Enzymatic synthesis of a complex sialylated glycoconjugate using specific glycosyltransferases.
• Assessment of NK cell-mediated cytotoxicity using human peripheral blood mononuclear cells (PBMC) as effectors and NK-sensitive/resistant cell lines as targets.

Main Results:

• The synthesized ergot alkaloid glycosides demonstrated significant immunomodulatory activity.
• Addition of these glycoconjugates potentiated PBMC cytotoxicity against both NK-sensitive and NK-resistant target cells.
• Glycoconjugates of elymoclavine specifically enhanced cytotoxicity against NK-resistant targets, while DH-lysergol derivatives potentiated activity against NK-sensitive targets.

Conclusions:

• Novel glycosides of ergot alkaloids exhibit potent immunomodulatory effects.
• The specific carbohydrate modifications influence the activity profile against different target cells.
• These findings suggest potential applications of ergot alkaloid glycosides in modulating NK cell-mediated immune responses.