Lisofylline

Lisofylline
Skeletal formula of lisofylline
Space-filling model of the lisofylline molecule
Clinical data
Other names1-(5-Hydroxyhexyl)-3,7-dimethylxanthine (HDX)
Identifiers
IUPAC name
  • 1-[(5R)-5-Hydroxyhexyl]-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H20N4O3
Molar mass280.328 g·mol−1
3D model (JSmol)
SMILES
  • O=C2N(c1ncn(c1C(=O)N2CCCC[C@H](O)C)C)C
InChI
  • InChI=1S/C13H20N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8-9,18H,4-7H2,1-3H3/t9-/m1/s1 checkY
  • Key:NSMXQKNUPPXBRG-SECBINFHSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Lisofylline (LSF) is a synthetic small molecule with novel anti-inflammatory properties. LSF can effectively prevent type 1 diabetes in preclinical models and improves the function and viability of isolated or transplanted pancreatic islets. It is a metabolite of pentoxifylline.

As well, LSF improves cellular mitochondrial function and blocks interleukin-12 (IL-12) signaling and STAT-4 activation in target cells and tissues. IL-12 and STAT-4 activation are important pathways linked to inflammation and autoimmune damage to insulin producing cells. Therefore, LSF and related analogs could provide a new therapeutic approach to prevent or reverse type 1 diabetes. LSF also directly reduces glucose-induced changes in human kidney cells suggesting that LSF and analogs have the potential to treat the complications associated with diabetes.

Synthesis

The R enantiomer of the pentoxyfylline analogue in which the ketone has been reduced to an alcohol shows enhanced activity as an inhibitor of acetyl CoA over the parent drug.

Lisofylline synthesis: U.S. Patent 5,567,704 NB[1][2][3][4][5][6][7]


For analogs see:[8]

Further reading

  • DE 3942872, Aretz, Werner; Furrer, Harald & Gebert, Ulrich et al., "Verfahren zur enantioselektiven Darstellung von (ω-1)-Hydroxyalkylxanthinen [Method for the enantioselective preparation of(ω-1)-hydroxyalkylxanthines]", published 1991-06-27, assigned to Hoechst AG 
  • US 5310666, Aretz, Werner; Furrer, Harald & Gebert, Ulrich et al., "Process for the enantioselective preparation of (β-1)-hydroxyalkylxanthines by reduction using Rhodotorula rubra", published 1994-05-10, assigned to Hoechst AG 
  • WO 9531450, Klein, J. Peter; Leigh, Alistair J. & Michnick, John et al., "Asymmetric synthesis of chiral secondary alcohols", published 1995-11-23, assigned to Cell Therapeutics Inc. 

References

  1. ↑ Matteson DS, Sadhu KM, Peterson ML (1986). "99% Chirally selective synthesis via pinanediol boronic esters: Insect pheromones, diols, and an amino alcohol". Journal of the American Chemical Society. 108 (4): 810. doi:10.1021/ja00264a039.
  2. ↑ Matteson DS, Ray R, Rocks RR, Tsai DJ (1980). "Directed chiral synthesis with pinanediol boronic esters". Journal of the American Chemical Society. 102 (25): 7590. doi:10.1021/ja00545a046.
  3. ↑ Matteson DS, Jesthi PK, Sadhu KM (1997). "Asymmetric synthesis of alkylarylcarbinols via reaction of a chiral pinanediol alkylboronic ester with arylmethyl chlorides". Tetrahedron: Asymmetry. 8 (23): 3843. doi:10.1016/S0957-4166(97)00565-X.
  4. ↑ Matteson DS, Jesthi PK, Sadhu KM (1984). "Synthesis and properties of pinanediol .alpha.-amido boronic esters". Organometallics. 3 (8): 1284. doi:10.1021/om00086a024.
  5. ↑ Matteson DS (1988). "Asymmetric synthesis with boronic esters". Accounts of Chemical Research. 21 (8): 294–300. doi:10.1021/ar00152a002.
  6. ↑ Matteson DS (October 2013). "Boronic esters in asymmetric synthesis". The Journal of Organic Chemistry. 78 (20): 10009–23. doi:10.1021/jo4013942. PMID 23875690.
  7. ↑ Scott HK, Aggarwal VK (November 2011). "Highly enantioselective synthesis of tertiary boronic esters and their stereospecific conversion to other functional groups and quaternary stereocentres". Chemistry. 17 (47): 13124–32. doi:10.1002/chem.201102581. PMID 22052475.
  8. ↑ Cui P, Macdonald TL, Chen M, Nadler JL (July 2006). "Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes". Bioorganic & Medicinal Chemistry Letters. 16 (13): 3401–5. doi:10.1016/j.bmcl.2006.04.036. PMID 16650991.
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