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 of the structural formula of Formula VIID:
wherein:
Ar is aryl or heteroaryl;
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; and
R 1 is either:
alkyl having 1 or 2 carbons, or
(CH 2 ) n X wherein n is an integer from 1 to 5, and X is selected from the group consisting of OR 2 and NR 2 R 2 , wherein each R 2 is independently either H or (CH 2 ) n CH 3 where n is from 0 to 4;
wherein, optionally, one or more hydrogens are replaced by fluorine atoms in an alkyl chain attached to N;
and pharmaceutically acceptable salts, hydrates, and optical isomers thereof.
2. A compound of claim 1 , wherein OR is 5-methoxy, R 1 is (CH 2 ) 3 OH, and Ar is 4-pyridyl.
3. A compound of claim 1 , wherein OR is 5-methoxy, R 1 is (CH 2 ) 2 CF 2 NH 2 , and Ar is 4-pyridyl.
4. A compound of claim 1 , wherein OR is 5-methoxy, R 1 is (CH 2 ) 3 NHCF 3 , and Ar is 4-pyridyl.
5. A compound of claim 1 , wherein the compound has the structural formula of Formula VIII:
6. A compound of claim 1 , wherein the compound has the structural formula of Formula IX:
7. A compound of claim 1 , wherein the compound has the structural formula of Formula X:
8. A compound of the structural formula of Formula VIIE:
wherein:
Ar is aryl or heteroaryl;
O is attached at the 6-position; and
R 1 is either:
alkyl having 1 or 2 carbons; or
(CH 2 ) n X wherein n is an integer from 1 to 5, and X is selected from OR 2 or NR 2 R 2 , wherein each R 2 is independently either H, unsubstituted alkyl having from 1 to 5 carbons, or fluorinated alkyl having from 1 to 5 carbons and from 2 to 11 fluorine atoms;
and pharmaceutically acceptable salts, hydrates, and optical isomers thereof.
9. A compound of claim 8 , wherein:
R is CH 3 ;
R 1 is CH 3 ; and
Ar is 4-pyridyl.
10. A compound of claim 8 , wherein:
R is CH 3 ;
R 1 is (CH 2 ) 3 OH; and
Ar is 4-pyridyl.
11. A compound of claim 8 , wherein:
R is CH 3 ;
R 1 is (CH 2 ) 2 CF 2 NH 2 ; and
Ar is 4-pyridyl.
12. A compound of 3-(2-hydroxypropyl-5-methoxy-indole-3-yl)-1-(4-pyridinyl)-2-propen-1-one (402q).
13. A method of inducing cell death in at least one cell, the method comprising:
introducing an effective amount of a compound of claim 1 to at least one cell and inducing cell death.
14. The method of claim 13 , wherein the cell is a cancer cell.
15. The method of claim 13 , wherein the cell is a glioblastoma cell.
16. The method of claim 13 , wherein the cell is a mammal cell.
17. The method of claim 13 , wherein the cell is a human cell.
18. 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 .
19. A pharmaceutical composition comprising:
a pharmacologically effective amount of a compound of claim 1 ; and
a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier.
20. A pharmaceutical composition comprising:
a pharmacologically effective amount of a compound of claim 8 ; and
a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier.