Materials and Methods Useful to Induce Vacuolization, Cell Death, or a Combination Thereof
The present invention provides materials and methods to induce cell death by methuosis, a non-apoptotic cell death mechanism, to induce vacuolization without cell death, or to induce cell death without vacuolization. Small molecules herein are useful for treating cell proliferation disorders or anomalies, particularly, but not exclusively, cancer. Methods related to the research and pharmaceutical use of the small molecules are also provided herein.
1. A compound comprising the structural formula of Formula VIIB:
wherein:
O is attached at any one of positions 4, 5, 6, or 7;
R is alkyl having from 1 to 6 carbon atoms either linear or branched;
R 1 is either:
alkyl having 2 carbon atoms further substituted at its terminus with a (CO)O-alkyl, (CO)O-aryl, or (CO)O-aralkyl moiety, or
alkyl having 3 to 6 carbon atoms either linear or branched, aryl, heteroaryl, aralkyl, or heteroaralkyl having from 6 to 12 carbon atoms; and
Ar is aryl or heteroaryl;
and pharmaceutically acceptable salts, hydrates, and optical isomers thereof.
2. A compound of claim 1 , wherein O is attached at the 5-position.
3. A compound of claim 1 , wherein:
R is methyl;
R 1 is n-propyl; and
Ar is 4-pyridyl.
4. A compound of claim 1 having the structural formula of Formula IIIA:
wherein R is selected from the group consisting of n-propyl, isopropyl, and isobutyl.
5. A compound comprising the structural formula of Formula VIIC:
wherein:
O is attached at any of positions 4, 5, 6, or 7;
R is alkyl having from 1 to 6 carbons either linear or branched;
R 1 is an electron-withdrawing group selected from the group consisting of halide; fluorinated alkyl; nitro; cyano; and (CO)R 2 , (CO)OR 2 or (CO)NHR 2 , when R 2 is selected from the group consisting of alkyl from 1 to 6 linear carbon atoms, aryl, heteroaryl, and aralkyl or heteroalkyl having from 6 to 12 carbon atoms; and
Ar is aryl or heteroaryl;
and pharmaceutically acceptable salts, hydrates, and optical isomers thereof.
6. A compound of claim 5 , wherein O is attached at the 5-position.
7. A compound of claim 5 wherein:
R is methyl;
R 1 is trifluoromethyl; and
Ar is 4-pyridyl.
8. A compound of claim 7 , wherein O is attached at the 5-position, the compound having the structural formula of Formula VI:
9. A compound of claim 5 , wherein the compound has the structural formula of Formula IIIB:
wherein R is an electron-withdrawing group selected from the group consisting of CF 3 and —COOR 2 , wherein R 2 is methyl, ethyl, or n-propyl.
10. A compound of claim 5 , wherein the compound has the structural formula of Formula IV:
wherein R is selected from the group consisting of methyl, ethyl, and n-propyl.
11. A compound of claim 5 , wherein the compound has the structural formula of Formula V:
12. A pharmaceutical composition comprising:
a pharmacologically effective amount of a compound of claim 1 ; and
a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier.
13. A pharmaceutical composition comprising:
a pharmacologically effective amount of a compound of claim 5 ; and
a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier.
14. A method of inducing vacuolization in at least one cell comprising:
introducing an effective amount of a compound of claim 1 to at least one cell and causing vacuolization in the cell, wherein cell death does not occur.
15. The method of claim 14 , wherein the cell is a cancer cell.
16. The method of claim 14 , wherein the cell is a glioblastoma cell.
17. The method of claim 14 , wherein the cell is a mammalian cell.
18. The method of claim 14 , wherein the cell is a human cell.
19. A method of inducing cell death in at least one cell comprising:
introducing an effective amount of a compound of claim 5 to at least one cell and inducing cell death.
20. The method of claim 19 , wherein the cell is a cancer cell.
21. The method of claim 19 , wherein the cell is a glioblastoma cell.
22. The method of claim 19 , wherein the cell is a mammalian cell.
23. The method of claim 19 , wherein the cell is a human cell.
24. A method of disrupting tubulin polymerization in a cell comprising administering to a cell an effective amount of a compound of claim 5 , and disrupting tubulin polymerization in the cell.
25. A method of ameliorating the effects of cancer in a mammal in need of such amelioration, comprising administering to a subject a pharmacologically effective amount of a compound of claim 1 .
26. A method of ameliorating the effects of cancer in a mammal in need of such amelioration, comprising administering to a subject having cancer a pharmacologically effective amount of a compound of claim 5 and ameliorating the effects of the cancer.
27. A composition comprising a compound of claim 1 and a therapeutic agent capable of inducing cell death.
28. The composition of claim 27 , wherein the therapeutic agent comprises an anti-cancer agent.