Iminosugar-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Potential Anti-Pancreatic Cancer Agents

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Nicotinamide phosphoribosyltransferase (NAMPT) is overexpressed in pancreatic cancer, making it a promising therapeutic target.
• Existing NAMPT inhibitors face challenges due to severe haematological toxicity observed in clinical trials.
• Development of novel, safer NAMPT inhibitors is crucial for effective pancreatic cancer treatment.

Purpose of the Study:

• To synthesize and evaluate novel β-d-iminoribofuranosides as potential NAMPT inhibitors for pancreatic cancer.
• To assess the contribution of the iminosugar moiety to the biological activity and properties of these compounds.
• To investigate the compounds' efficacy in inhibiting NAMPT, reducing pancreatic tumor cell viability, and depleting intracellular NAD+.

Main Methods:

• Synthesis of ten novel β-d-iminoribofuranosides with heterocycle-based chains linked to the anomeric position.
• In vitro assays to evaluate NAMPT inhibition.
• Assessment of pancreatic tumor cell viability and intracellular NAD+ depletion.
• Comparative analysis with analogues lacking the iminosugar moiety.

Main Results:

• The synthesized iminosugar derivatives were tested for their biological activity.
• Evaluation included NAMPT inhibition, pancreatic tumor cell viability, and intracellular NAD+ depletion.
• The study compared the activity of iminosugar-containing compounds with their non-carbohydrate counterparts.

Conclusions:

• The synthesized β-d-iminoribofuranosides represent a novel class of potential NAMPT inhibitors.
• This study provides the first assessment of the iminosugar moiety's contribution to the antitumor properties of these agents.
• The findings pave the way for developing new pancreatic cancer therapeutics with potentially improved safety profiles.