Ceramide derivatives as modulators of immunity and autoimmunity
View Patent ↗α-Galactosylceramides and glycosylceramides (“ceramide-like glycolipids”) that modulate NK T cells. The ceramide-like glycolipids vary in the cytokines induced in NK T cells and vary in the antigen-presenting cells that are capable of efficiently presenting the compounds to NK T cells. Pharmaceutical compositions of the ceramide-like glycolipids are provided, as are pharmaceutical compositions of the ceramide-like glycolipids combined with dendritic cells. Methods utilizing the ceramide-like glycolipids in vaccines, to activate NK T cells, to stimulate the immune system, and to treat mammals are also provided. The invention also provides methods of evaluating a compound for its ability to activate an NK T cell in the presence of a cell expressing a CD1d protein.
1. An α-galactosylceramide of Formula I:
wherein
R1 is a C 6 -C 27 alkane or alkene wherein (i) the C 6 -C 27 alkane or alkene is substituted with a C 5 -C 15 cycloalkane, C 5 -C 15 cycloalkene, heterocycle, or aromatic ring or (ii) the C 6 -C 27 alkane or alkene includes, within the C 6 -C 27 alkyl or alkenyl chain, a C 5 -C 15 cycloalkane, C 5 -C 15 cycloalkene, heterocycle, or aromatic ring; and
R2 is one of the following (a)-(e):
(a) —CH 2 (CH 2 ) X CH 3 ,
(b) —CH(OH)(CH 2 ) X CH 3 ,
(c) —CH(OH)(CH 2 ) X CH(CH 3 ) 2 ,
(d) —CH═CH(CH 2 ) X CH 3 ,
(e) —CH(OH)(CH 2 ) X CH(CH 3 )CH 2 CH 3 ,
wherein X is an integer ranging from 5-17.
2. The α-galactosylceramide of claim 1 , wherein R2 is —CH(OH)(CH 2 ) 13 CH 3 .
3. The α-galactosylceramide of claim 1 , wherein R1 is substituted with oxo; hydroxy; halogen; —OC(O)R 5 ; —OR 5 ; —C(O)R 5 ; or —N(R 5 ) 2 ,
wherein each R 5 is independently hydrogen, C 1 -C 6 alkyl, or an aromatic ring optionally substituted with halogen, hydroxy, —OC(O)R 6 , —OR 6 , —C(O)R 6 , or —N(R 6 ) 2 ,
wherein each R 6 is independently hydrogen or C 1 -C 6 alkyl.
4. An α-galactosylceramide of Formula I:
wherein R1 is selected from the group consisting of
where ( ) represent the point of attachment of R1 to the compound of Formula I, and
R2 is one of the following (a)-(e):
(a) —CH 2 (CH 2 ) X CH 3 ,
(b) —CH(OH)(CH 2 ) X CH 3 ,
(c) —CH(OH)(CH 2 ) X CH(CH 3 ) 2 ,
(d) —CH═CH(CH 2 ) X CH 3 ,
(e) —CH(OH)(CH 2 ) X CH(CH 3 )CH 2 CH 3 ,
wherein X is an integer ranging from 5-17.
5. The α-galactosylceramide of claim 4 , wherein R2 is —CH(OH)(CH 2 ) 13 CH 3 .
6. An α-galactosylceramide of Formula I:
wherein
R1 is selected from the group consisting of —C(═O)OCH 2 CH 3 , —(CH 2 ) 6 CH 3 , —(CH 2 ) 4 Cl, —(CH 2 ) 16 CH 3 , —(CH 2 ) 5 CH 3 , —(CH 2 ) 2 CH 3 , —(CH 2 ) 4 CH 3 , —(CH 2 ) 8 CH 3 , —(CH 2 ) 10 CH 3 , and —(CH 2 ) 12 CH 3 ; and
wherein R2 is —CH(OH)(CH 2 ) 13 CH 3 .
7. An α-galactosylceramide of Formula I:
wherein R1 is a linear or branched C 2 -C 27 alkene with at least two C═C bonds or R1 is C(OH)—R3 wherein R3 is a linear or branched C 2 -C 26 alkene with at least two C═C bonds, wherein R2 is —CH(OH)(CH 2 )xCH 3 , and wherein X is an integer ranging from 5-17.
8. The α-galactosylceramide of claim 7 , wherein R1 is a linear or branched alkene with at least two C═C bonds, and R2 is —CH(OH)(CH 2 )xCH 3 , wherein X is an integer ranging from 5-17.
9. The α-galactosylceramide of claim 8 , wherein R2 is —CH(OH)(CH 2 ) 13 CH 3 .
10. The α-galactosylceramide of claim 9 , wherein said α-galactosylceramide having the following formula:
11. The α-galactosylceramide of claim 9 , wherein said α-galactosylceramide having the following formula: