Procaspase-activating compounds and methods
View Patent ↗The invention provides compounds and compositions useful for the modulation of certain enzymes. The compounds and compositions can induce of cell death, particularly cancer cell death. The invention also provides methods for the synthesis and use of the compounds and compositions, including the use of compounds and compositions in therapy for the treatment of cancer and selective induction of apoptosis in cells.
1. A method of treating a cancer cell comprising (a) identifying a susceptibility to treatment of a cancer cell with a procaspase activator compound; and (b) exposing a cancer cell to an effective amount of a procaspase activator compound that activates procaspase-3, wherein the procaspase activator compound is a compound Formula I:
wherein R 1 is
n is 1, 2, 3, or 4; and
each R 2 is alkyl; or two R 2 groups form an ortho-fused benzo group;
or a pharmaceutically acceptable salt or solvate thereof; and
treating a cancer cell is defined as killing the cancer cell or inhibiting the cancer cell from proliferating, and the cancer cell is a leukemia cell.
2. The method of claim 1 wherein each R 2 is t-butyl.
3. The method of claim 1 wherein n is 1 or 2.
4. The method of claim 1 wherein n is 2 and each R 2 is t-butyl.
5. The method of claim 1 wherein the compound of Formula I is:
6. The method of claim 1 wherein the compound of Formula I is in the form of a composition comprising a pharmaceutically acceptable diluent, excipient, or carrier.
7. The method of claim 6 wherein the composition comprises a compound of Formula I at a concentration of about 10 nM to about 100 μM.
8. The method of claim 6 wherein the composition comprises a compound of Formula I at a concentration of about 200 nM to about 5 μM.
9. The method of claim 1 wherein the lethality of the compound of Formula I is selective for the cancer cell over non-cancerous cells.
10. A method of inducing apoptosis in a leukemia cell comprising administering to a cancer cell an effective apoptotic amount of a compound of Formula I:
wherein
R 1 is
n is 1, 2, 3, or 4; and
each R 2 is alkyl; or two R 2 groups form an ortho-fused benzo group;
or a pharmaceutically acceptable salt or solvate thereof;
thereby killing the leukemia cell.
11. The method of claim 10 wherein each R 2 is t-butyl.
12. The method of claim 10 wherein n is 1 or 2.
13. The method of claim 10 wherein n is 2 and each R 2 is t-butyl.
14. The method of claim 10 wherein the compound of Formula I is:
15. The method of claim 10 wherein the compound of Formula I is in the form of a composition comprising a pharmaceutically acceptable diluent, excipient, or carrier.
16. The method of claim 15 wherein the composition comprises a compound of Formula I at a concentration of about 10 nM to about 100 μM.
17. The method of claim 15 wherein the composition comprises a compound of Formula I at a concentration of about 200 nM to about 5 μM.