Prodrugs of glutamine analogs
Prodrugs of glutamine analogs, such as prodrugs of acivicin, are disclosed.
1. A prodrug of acivicin, or a pharmaceutically acceptable salt or ester thereof, the prodrug having a structure of formula (I):
wherein:
R 1 is C 3-6 branched alkyl; and
R 2 is —C(═O)—Y—(CR 3 R 4 ) m —NR 5 R 6 ;
Y is a bond;
m=1;
R 3 and R 4 are independently H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl, aryl or substituted aryl, or
R 5 and R 6 are independently H and alkyl;
R 2 ′ is selected from the group consisting of H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, substituted or unsubstituted succinyl, and substituted or unsubstituted glutamyl, or
R 2 and R 2 ′ together form a ring structure comprising C(═O)G-C(═O)—, wherein G is selected from the group consisting of C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene, C 5 -C 8 cycloalkylene, C 5 -C 14 heteroarylene, and bivalent C 4 -C 10 heterocycle, each of which can be optionally substituted; or
R 1 and R 2 ′ together form a 4-to 6-membered heterocylic ring comprising the oxygen atom adjacent to R 1 and the nitrogen atom adjacent to R 2 ′; and
X is selected from the group consisting of halogen, cyano, hydroxyl, alkoxyl, and acetate.
2. The prodrug of claim 1 , wherein:
R 3 is H;
R 4 is
or C 1 -C 6 alkyl; and
R 5 and R 6 are each H.
3. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
4. A pharmaceutical composition comprising a compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.