Lisofylline

Lisofylline
Clinical data
Other names	1-(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	100324-81-0 ;
PubChem CID	501254;
ChemSpider	438549 ;
UNII	L1F2Q2X956;
ChEBI	CHEBI:143527;
ChEMBL	ChEMBL1411 ;
CompTox Dashboard (EPA)	DTXSID7058709 ;
Chemical and physical data
Formula	C13H20N4O3
Molar mass	280.32 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	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 ; Key:NSMXQKNUPPXBRG-SECBINFHSA-N ;
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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]

DE 3942872; eidem, U.S. Patent 5,310,666 (1991, 1994 both to Hoechst). Asymmetric synthesis: J. P. Klein et al., WO 9531450 (1995 to Cell Therapeutics).

For analogs see:[8]

References

Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. (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.
Matteson, D. S.; Ray, R. (1980). "Directed chiral synthesis with pinanediol boronic esters". Journal of the American Chemical Society. 102 (25): 7590. doi:10.1021/ja00545a046.
Kabalka, G. W.; Li, N. S.; Yu, S. (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.
Matteson, D. S.; Jesthi, P. K.; Sadhu, K. M. (1984). "Synthesis and properties of pinanediol .alpha.-amido boronic esters". Organometallics. 3 (8): 1284. doi:10.1021/om00086a024.
Matteson, D. S. (1988). "Asymmetric synthesis with boronic esters". Accounts of Chemical Research. 21 (8): 294. doi:10.1021/ar00152a002.
Matteson, D. S. (2013). "Boronic Esters in Asymmetric Synthesis". The Journal of Organic Chemistry. 78 (20): 10009–23. doi:10.1021/jo4013942. PMID 23875690.
Scott, H. K.; Aggarwal, V. K. (2011). "Highly Enantioselective Synthesis of Tertiary Boronic Esters and their Stereospecific Conversion to other Functional Groups and Quaternary Stereocentres". Chemistry: A European Journal. 17 (47): 13124. doi:10.1002/chem.201102581.
Cui, P.; MacDonald, T. L.; Chen, M.; Nadler, J. L. (2006). "Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes". Bioorganic & Medicinal Chemistry Letters. 16 (13): 3401. doi:10.1016/j.bmcl.2006.04.036. PMID 16650991.

External links

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[1] Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. (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, D. S.; Ray, R. (1980). "Directed chiral synthesis with pinanediol boronic esters". Journal of the American Chemical Society. 102 (25): 7590. doi:10.1021/ja00545a046.

[3] Kabalka, G. W.; Li, N. S.; Yu, S. (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, D. S.; Jesthi, P. K.; Sadhu, K. M. (1984). "Synthesis and properties of pinanediol .alpha.-amido boronic esters". Organometallics. 3 (8): 1284. doi:10.1021/om00086a024.

[5] Matteson, D. S. (1988). "Asymmetric synthesis with boronic esters". Accounts of Chemical Research. 21 (8): 294. doi:10.1021/ar00152a002.

[6] Matteson, D. S. (2013). "Boronic Esters in Asymmetric Synthesis". The Journal of Organic Chemistry. 78 (20): 10009–23. doi:10.1021/jo4013942. PMID 23875690.

[7] Scott, H. K.; Aggarwal, V. K. (2011). "Highly Enantioselective Synthesis of Tertiary Boronic Esters and their Stereospecific Conversion to other Functional Groups and Quaternary Stereocentres". Chemistry: A European Journal. 17 (47): 13124. doi:10.1002/chem.201102581.

[8] Cui, P.; MacDonald, T. L.; Chen, M.; Nadler, J. L. (2006). "Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes". Bioorganic & Medicinal Chemistry Letters. 16 (13): 3401. doi:10.1016/j.bmcl.2006.04.036. PMID 16650991.