Proteasome inhibitors
Disclosed herein are compounds of Formula (I) that include a sulfonate ester, ester or ether group. Compounds of Formula (I) can be included in pharmaceutical compositions, and can be used to treating and/or ameliorating a disease or condition, such as cancer, a microbial disease and/or inflammation.
1. A method for treating, alleviating or diagnosing a neoplastic disease comprising administering to a subject a therapeutically effective amount of a compound having the structure of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Formula (I) has the structure:
wherein:
R 1 has a structure selected from the group consisting of:
wherein R 4 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C 1-6 alkyl), heteroaryl, heteroaryl(C 1-6 alkyl), heterocyclyl, and heterocyclyl(C 1-6 alkyl), wherein R 4 can be optionally substituted with
wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and
Z 1 is selected from the group consisting of O, S, N═N, O(CH 2 ) 1-6 , S(O) 2 N(R 17 ), S(O) 2 N(R 17 )(CH 2 ) 1-6 , C(═O)N(R 17 ), N(R 17 )C(═O), N(R 17 )C(═O)(CH 2 ) 1-6 , N(R 17 )C(═O)O(CH 2 ) 1-6 , S(O) 2 , C(═O), (CH 2 ) 1-6 C(═O), O(CH 2 ) 1-6 C(═O), (CH 2 ) 1-6 N(R 17 )C(═O), CH═CH—C(═O)N(R 17 ), CH═CH—C(═O), O(CH 2 ) 1-6 O, O(CH 2 ) 1-6 and N(R 17a )C(═O)N(R 17b ), wherein R 17 , R 17a and R 17b are independently selected from the group consisting of H, C 1-4 alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC);
R 2 is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, aryl, and arylalkyl;
n is 1, 2 or 3;
E 1 and E 3 are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S;
E 2 is a substituted or unsubstituted N or —CH 2 — group;
E 4 is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N;
E 5 is NH 2 , OH or SH; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 92 g/mol; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 77 g/mol;
wherein the neoplastic disease is a cancer is selected from the group consisting of: breast cancer, sarcoma, leukemia, ovarian cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, kidney cancer, endocrine cancer, melanoma, skin cancer, angiosarcoma, sinus cancer, esophageal cancer, uretal cancer, liver cancer, angioma, central nervous system (CNS) cancer, Mantle cell lymphoma, low IgM secreting lymphoma, Burkitt's lymphoma, B-NHL and Waldenstrom's Macroglobulinemia.
2. The method of claim 1 , wherein when R 1 is
R 4 has a molecular weight equal to or greater than 107 g/mol or when R 1 is
R 4 has a molecular weight equal to or greater than 92 g/mol.
3. The method of claim 1 , wherein when R 1 is
R 4 has a molecular weight equal to or greater than 122 g/mol or when R 1 is
R 4 has a molecular weight equal to or greater than 107 g/mol.
4. The method of claim 1 , wherein R 1 has a structure selected from the group consisting of:
wherein:
R 5a , R 5b , R 5c , R 5d , R 5e , R 9a , R 9b , R 9c , R 9d , R 9e , R 13a , R 13b , R 13c , R 13d and R 13e are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, C 2-24 alkenyl, C 2-24 alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 6a , R 6b , R 6c , R 10a , R 10b , R 10c , R 14a , R 14b and R 14c are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, C 2-24 alkenyl, C 2-24 alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 7a , R 7b , R 7c , R 11a , R 11b , R 11c , R 15a , R 15b and R 15c are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, C 2-24 alkenyl, C 2-24 alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 8a , R 8b , R 8c , R 8d , R 12a , R 12b , R 12c , R 12d , R 16a , R 16b , R 16c and R 16d are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, C 2-24 alkenyl, C 2-24 alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl and —S(═O) 2 O − ;
B, D and F are each independently selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
C, E and G are each independently selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl; and
Z 1 is selected from the group consisting of O, S, N═N, O(CH 2 ) 1-6 , S(O) 2 N(R 17 ), S(O) 2 N(R 17 )(CH 2 ) 1-6 , C(═O)N(R 17 ), N(R 17 )C(═O), N(R 17 )C(═O)(CH 2 ) 1-6 , N(R 17 )C(═O)O(CH 2 ) 1-6 , S(O) 2 , C(═O), (CH 2 ) 1-6 C(═O), O(CH 2 ) 1-6 C(═O), (CH 2 ) 1-6 N(R 17 )C(═O), CH═CH—C(═O)N(R 17 ), CH═CH—C(═O), O(CH 2 ) 1-6 O, O(CH 2 ) 1-6 and N(R 17a )C(═O)N(R 17b ), wherein R 17 , R 17a and R 17b are independently selected from the group consisting of H, C 1-4 alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC).
5. The method of claim 4 , wherein R 1 is
and R 5a , R 5b , R 5c , R 5d , and R 5e are each independently selected from the group consisting of: hydrogen, halo, nitro, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, and carboxy.
6. The method of claim 4 , wherein R 1 is
and B is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
7. The method of claim 4 , wherein R 1 is
and C is a mono-substituted, a poly-substituted or an unsubstituted heterocyclyl ring.
8. The method of claim 4 , wherein R 1 is
and C is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
9. The method of claim 4 , wherein R 1 is
and Z 1 is O or N═N.
10. The method of claim 4 , wherein R 1 is
and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
11. The method of claim 4 , wherein R 1 is
and A is a mono-substituted, a poly-substituted or an unsubstituted heteroaryl ring.
12. The method of claim 4 , wherein R 1 is
and R 9a , R 9b , R 9c , R 9d and R 9e are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, and hydroxy.
13. The method of claim 4 , wherein R 1 is
and D is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
14. The method of claim 4 , wherein R 1 is
and E is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
15. The method of claim 4 , wherein R 1 is
and Z 1 is selected from the group consisting of O, O(CH 2 ) 1-6 and N═N.
16. The method of claim 4 , wherein R 1 is
and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
17. The method of claim 4 , wherein R 1 is
R 13a , R 13b , R 13c , R 13d and R 13e are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, carboxy and hydroxy.
18. The method of claim 4 , wherein R 1 is
and F is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
19. The method of claim 4 , wherein R 1 is
and G is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
20. The method of claim 4 , wherein R 1 is
and Z 1 is O or N═N.
21. The method of claim 4 , wherein R 1 is
and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
22. The method of claim 4 , wherein: R 1 is selected from the group consisting of:
23. The method of claim 4 , wherein: R 1 is selected from the group consisting of:
24. The method of claim 4 , wherein R 1 is selected from the group consisting of:
25. The method of claim 1 , wherein R 3 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, aryl, and arylalkyl.
26. The method of claim 25 , wherein R 2 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted C 1 -C 12 alkyl, a mono-substituted, a poly-substituted or an unsubstituted C 3 -C 12 cycloalkanyl, a mono-substituted, a poly-substituted or an unsubstituted C 3 -C 12 cycloalkenyl and a mono-substituted, a poly-substituted or an unsubstituted aryl; and R 3 is a mono-substituted, a poly-substituted or an unsubstituted C 1-6 alkyl.
27. The method of claim 26 , wherein n is 2.
28. The method of claim 1 , wherein the cancer is selected from the group consisting of multiple myeloma, a colorectal carcinoma, a prostate carcinoma, a breast adenocarcinoma, a non-small cell lung carcinoma, an ovarian carcinoma and a melanoma.
29. The method of claim 1 , wherein the cancer is a drug-resistant cancer.
30. The method of claim 29 , wherein the drug-resistant cancer may display at least one of the following: elevated levels of the P-glycoprotein efflux pump, increased expression of the multidrug-resistance associated protein 1 encoded by MRP1, reduced drug uptake, alteration of the drug's target or increasing repair of drug-induced DNA damage, alteration of the apoptotic pathway or the activation of cytochrome P450 enzymes.
31. The method of claim 29 , wherein the drug-resistant cancer is leukemia or a sarcoma.
32. A method for inhibiting NF-κB activity comprising administering to a subject a therapeutically effective amount of a compound having the structure of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Formula (I) has the structure:
wherein:
R 1 has a structure selected from the group consisting of:
wherein R 4 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C 1-6 alkyl), heteroaryl, heteroaryl(C 1-6 alkyl), heterocyclyl, and heterocyclyl(C 1-6 alkyl), wherein R 4 can be optionally substituted with
wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and
Z 1 is selected from the group consisting of O, S, N═N, O(CH 2 ) 1-6 , S(O) 2 N(R 17 ), S(O) 2 N(R 17 )(CH 2 ) 1-6 , C(═O)N(R 17 ), N(R 17 )C(═O), N(R 17 )C(═O)(CH 2 ) 1-6 , N(R 17 )C(═O)O(CH 2 ) 1-6 , S(O) 2 , C(═O), (CH 2 ) 1-6 C(═O), O(CH 2 ) 1-6 C(═O), (CH 2 ) 1-6 N(R 17 )C(═O), CH═CH—C(═O)N(R 17 ), CH═CH—C(═O), O(CH 2 ) 1-6 O, O(CH 2 ) 1-6 and N(R 17a )C(═O)N(R 17b ), wherein R 17 , R 17a and R 17b are independently selected from the group consisting of H, C 1-4 alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC);
R 2 is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, aryl, and arylalkyl;
n is 1, 2 or 3;
E 1 and E 3 are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S;
E 2 is a substituted or unsubstituted N or —CH 2 — group;
E 4 is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N;
E 5 is NH 2 , OH or SH; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 92 g/mol; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 77 g/mol.
33. A method of inhibiting proteasome activity comprising administering to a subject a therapeutically effective amount of a compound having the structure of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Formula (I) has the structure:
wherein:
R 1 has a structure selected from the group consisting of:
wherein R 4 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C 1-6 alkyl), heteroaryl, heteroaryl(C 1-6 alkyl), heterocyclyl, and heterocyclyl(C 1-6 alkyl), wherein R 4 can be optionally substituted with
wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and
Z 1 is selected from the group consisting of O, S, N═N, O(CH 2 ) 1-6 , S(O) 2 N(R 17 ), S(O) 2 N(R 17 )(CH 2 ) 1-6 , C(═O)N(R 17 ), N(R 17 )C(═O), N(R 17 )C(═O)(CH 2 ) 1-6 , N(R 17 )C(═O)O(CH 2 ) 1-6 , S(O) 2 , C(═O), (CH 2 ) 1-6 C(═O), O(CH 2 ) 1-6 C(═O), (CH 2 ) 1-6 N(R 17 )C(═O), CH═CH—C(═O)N(R 17 ), CH═CH—C(═O), O(CH 2 ) 1-6 O, O(CH 2 ) 1-6 and N(R 17a )C(═O)N(R 17b ), wherein R 17 , R 17a and R 17b are independently selected from the group consisting of H, C 1-4 alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC);
R 2 is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, aryl, and arylalkyl;
n is 1, 2 or 3;
E 1 and E 3 are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S;
E 2 is a substituted or unsubstituted N or —CH 2 — group;
E 4 is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N;
E 5 is NH 2 , OH or SH; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 92 g/mol; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 77 g/mol.
34. A method for inhibiting the growth of a cancer cell comprising contacting the cancer cell with a therapeutically effective amount of a compound having the structure of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Formula (I) has the structure:
wherein:
R 1 has a structure selected from the group consisting of:
wherein R 4 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C 1-6 alkyl), heteroaryl, heteroaryl(C 1-6 alkyl), heterocyclyl, and heterocyclyl(C 1-6 alkyl), wherein R 4 can be optionally substituted with
wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and
Z 1 is selected from the group consisting of O, S, N═N, O(CH 2 ) 1-6 , S(O) 2 N(R 17 ), S(O) 2 N(R 17 )(CH 2 ) 1-6 , C(═O)N(R 17 ), N(R 17 )C(═O), N(R 17 )C(═O)(CH 2 ) 1-6 , N(R 17 )C(═O)O(CH 2 ) 1-6 , S(O) 2 , C(═O), (CH 2 ) 1-6 C(═O), O(CH 2 ) 1-6 C(═O), (CH 2 ) 1-6 N(R 17 )C(═O), CH═CH—C(═O)N(R 17 ), CH═CH—C(═O), O(CH 2 ) 1-6 O, O(CH 2 ) 1-6 and N(R 17a )C(═O)N(R 17b ), wherein R 17 , R 17a and R 17b are independently selected from the group consisting of H, C 1-4 alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC);
R 2 is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, aryl, and arylalkyl;
n is 1, 2 or 3;
E 1 and E 3 are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S;
E 2 is a substituted or unsubstituted N or —CH 2 — group;
E 4 is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N;
E 5 is NH 2 , OH or SH; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 92 g/mol; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 77 g/mol; wherein the cancer cell is selected from the group consisting of a breast cancer cell, a sarcoma cell, a leukemia cell, an ovarian cancer cell, a bladder cancer cell, a prostate cancer cell, a colon cancer cell, a rectal cancer cell, a stomach cancer cell, a lung cancer cell, a lymphoma cell, a multiple myeloma cell, a pancreatic cancer cell, a kidney cancer cell, an endocrine cancer cell, a melanoma cell, a skin cancer cell, an angiosarcoma cell, a sinus cancer cell, an esophageal cancer cell, an uretal cancer cell, a liver cancer cell, an angioma cell and a central nervous system (CNS) cancer cell.