Proteasome inhibitors for selectively inducing apoptosis in cancer cells
The subject invention concerns compounds having activity as inhibitors of proteasomes and methods of using the subject compounds. In one embodiment, a compound of the invention has the chemical structure shown in formula I: or a pharmaceutically acceptable salt or hydrate thereof. In another embodiment, a compound of the invention has the chemical structure shown in formula II: or a pharmaceutically acceptable salt or hydrate thereof.
1. A method of treating an oncological disorder in a person or animal, said method comprising administering to the person or animal an effective amount of a proteasome inhibitor compound having the chemical structure shown in formula I:
wherein
R 1 is an organic cyclic ring structure bonded to a sulfonamide structure;
R 2 is H, halogen, alkyl, —NR 6 R 7 , or heteroalkyl;
R 3 is H, halogen, —OH, —O-alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NO 2 , —NH 2 or substituted amines;
R 4 is H, alkyl, heteroalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of —NO 2 , alkyl, heteroalkyl, aryl, or heteroaryl, or halogen;
R 5 is H, —OH, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —O-alkyl, —O-aryl, heteroalkyl, —NO 2 , —NH 2 , or substituted amine; and
R 6 and R 7 are independently H, O, alkyl, aryl, heterocycloalkyl, or heteroaryl, or together can form a heterocycloalkyl or a heteroaryl, any of which can be optionally substituted with one or more of —NO 2 , alkyl, heteroalkyl, aryl, or halogen;
or a pharmaceutically acceptable salt thereof, wherein the oncological disorder is selected from among ovarian cancer, pancreatic cancer, breast cancer, lung cancer, prostate cancer, and multiple myeloma.
2. A method of inducing apoptosis in a cell or inhibiting chymotrypsin-like enzymatic activity in a cell, said method comprising contacting a cell in vivo with an effective amount of a proteasome inhibitor compound having the chemical structure shown in formula I:
wherein
R 1 is an organic cyclic ring structure bonded to a sulfonamide structure;
R 2 is H, halogen, alkyl, —NR 6 R 7 , or heteroalkyl;
R 3 is H, halogen, —OH, —O-alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NO 2 , —NH 2 or substituted amines;
R 4 is H, alkyl, heteroalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of —NO 2 , alkyl, heteroalkyl, aryl, or heteroaryl, or halogen;
R 5 is H, —OH, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —O-alkyl, —O-aryl, heteroalkyl, —NO 2 , —NH 2 , or substituted amine; and
R 6 and R 7 are independently H, O, alkyl, aryl, heterocycloalkyl, or heteroaryl, or together can form a heterocycloalkyl or a heteroaryl, any of which can be optionally substituted with one or more of —NO 2 , alkyl, heteroalkyl, aryl, or halogen;
or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 , wherein R 2 is NR 6 R 7 and has a chemical structure of:
4. The method of claim 2 , wherein R 2 is Cl or F.
5. The method of claim 2 , wherein R 4 is ethyl, methyl, butyl, —CH 2 -phenyl, —CH 2 -naphthyl, —CH 2 -4-nitro-phenyl, —CH 2 -4-methyl-phenyl, or —CH 2 -4-trifluoromethyl-phenyl.
6. The method of claim 2 , wherein R 1 has the chemical structure
wherein R 8 is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein R 8 can be substituted at any position with R′″;
wherein R′ and R″ are independently selected from H, alkyl, aryl, heterocycloalkyl, heteroaryl, alkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl or heteroarylcarbonyl, any of which can optionally be substituted with one or more halogen, alkyl, or alkoxy; and
R′″ is —NO 2 , —OH, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —O-alkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, or an amine (primary, secondary, or tertiary).
7. The method of claim 2 , wherein R 1 has the chemical structure
8. The method of claim 6 , wherein R′ and R″ are independently selected from H and the following:
wherein indicates the point of attachment.
9. The method of claim 2 , wherein the compound is
10. The method of claim 7 , wherein R′ and R″ are independently selected from H and the following:
wherein indicates the point of attachment.
11. The method of claim 2 , wherein the compound is
12. The method of claim 1 , wherein R 2 is NR 6 R 7 and has a chemical structure of:
13. The method of claim 1 , wherein R 2 is Cl or F.
14. The method of claim 1 , wherein R 4 is ethyl, methyl, butyl, —CH 2 -phenyl, —CH 2 -naphthyl, —CH 2 -4-nitro-phenyl, —CH 2 -4-methyl-phenyl, or —CH 2 -4-trifluoromethyl-phenyl.
15. The method of claim 1 , wherein R 1 has the chemical structure
wherein R 8 is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, wherein R 8 can be substituted at any position with R′″;
wherein R′ and R″ are independently selected from H, alkyl, aryl, heterocycloalkyl, heteroaryl, alkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl or heteroarylcarbonyl, any of which can optionally be substituted with one or more halogen, alkyl, or alkoxy; and
R′″ is —NO 2 , —OH, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —O-alkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, or an amine (primary, secondary, or tertiary).
16. The method of claim 1 , wherein R 1 has the chemical structure
17. The method of claim 8 , wherein R′ and R″ are independently selected from H and the following:
wherein indicates the point of attachment.
18. The method of claim 1 , wherein the compound is
19. The method of claim 10 , wherein R′ and R″ are independently selected from H and the following:
wherein indicates the point of attachment.
20. The method of claim 1 , wherein the compound is
21. The method of claim 2 , wherein the cell is an ovarian cancer cell, pancreatic cancer cell, breast cancer cell, lung cancer cell, prostate cancer cell, or multiple myeloma cell.