Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes.

Abstract

Lisofylline (LSF, 1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine) is an anti-inflammatory agent that protects beta-cells from Th1 cytokine-induced dysfunction and reduces the onset of Type 1 diabetes in non-obese diabetic (NOD) mice. Due to its low potency, poor oral bioavailability, and short half-life, the widespread clinical utility of LSF may be limited. Our goal has been to develop new agents based on the LSF structural motif that resolve the potency and pharmacokinetic liabilities of LSF. In this study, we have generated a focused library of LSF analogs that maintain the side chain (5-R-hydroxyhexyl) constant, while substituting a variety of nitrogen-containing heterocyclic substructures for the xanthine moiety of LSF. This library includes the xanthine-like (5-aza-7-deazaxanthine), as well as non-xanthine-like skeletons. The LSF analogs were evaluated in a pancreatic beta-cell line for the effects on apoptosis protection and insulin release. The metabolic stability of selected compounds was also tested.

• Authors: Peng Cui, Timothy L Macdonald, Meng Chen, Jerry L Nadler
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 16 Issue 13 Pg. 3401-5 (Jul 01 2006) ISSN: 0960-894X [Print] England
• PMID: 16650991 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Hypoglycemic Agents
• Insulin
• lisofylline
• Pentoxifylline

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line
• Chemoprevention
• Cytokines (pharmacology)
• Diabetes Mellitus, Type 1 (drug therapy, prevention & control)
• Drug Evaluation, Preclinical
• Hypoglycemic Agents (chemical synthesis, metabolism, pharmacology)
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (drug effects, metabolism)
• Mice
• Molecular Structure
• Pentoxifylline (analogs & derivatives, chemical synthesis, metabolism, pharmacology)
• Stereoisomerism