Materials and methods useful to induce cell death via methuosis
The present invention provides materials and methods to induce cell death by methuosis, a non-apoptotic cell death mechanism. 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 having the structure of Formula I:
wherein X and Y are independently absent or halogen, oxygen, azide, nitrogen, (CO)O, O(CO), O(CO)O, (CO)N, NH(CO), NH(CO)N, NH(CO)O, or O(CO)N;
wherein when X or Y is halogen or azide, then R is absent, and
wherein when X or Y is nitrogen, (CO)N, O(CO)N, or NH(CO)N, then two R groups are present;
wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or aralkyl;
wherein R 1 is hydrogen, alkyl, alkenyl, or alkynyl;
wherein Ar is heteroaryl;
wherein when XR is hydrogen and Y is absent, then R is not hydrogen or methyl; and
wherein when XR is halide and Y is absent, then R is not hydrogen;
and pharmaceutically acceptable salts, hydrates, and optical isomers thereof.
2. The compound of claim 1 , wherein XR is methoxy bound at the 5 position, YR is methyl, and R 1 is hydrogen.
3. A compound of claim 2 , wherein Ar is 4-pyridyl.
4. The compound of claim 1 , which is capable of inducing methuosis.
5. A method of inducing cell death in at least one cell, comprising introducing a compound of claim 1 to at least one cell and inducing cell death.
6. A method of claim 5 , wherein the at least one cell is a mammalian cell.
7. A method of claim 5 , wherein the at least one cell is drug-resistant.
8. A method of claim 5 , wherein the at least one cell is apoptosis-resistant.
9. A method of claim 5 , wherein the at least one cell is a cancer cell.
10. A method of claim 5 , wherein the at least one cell is a cancer stem cell.
11. A method of claim 5 , wherein the at least one cell is a human cell.
12. A method of inducing cell death in a mammal in need of such induction, comprising administering to a subject a pharmacologically effective amount of a compound of claim 1 .
13. The method of claim 12 , wherein the mammal is selected from the group consisting of: mouse; rat; guinea pig; rabbit; cat; dog; monkey; goat; cow; horse; and human.
14. 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 .
15. A method of claim 14 , wherein the cancer is selected from the group consisting of: brain, lung, pancreas, bone, bladder, colon, stomach, breast, prostate, ovary, central nervous system, or skin.
16. The method of claim 14 , wherein the mammal is selected from the group consisting of: mouse; rat; guinea pig; rabbit; cat; dog; monkey; goat; cow; horse; and human.
17. The method of claim 14 , wherein the method further comprises administering a second compound, adjuvant or additional therapeutic to the mammal.
18. A composition of matter comprising a compound of claim 1 and a cancer therapeutic.
19. A composition of claim 18 , wherein the cancer therapeutic is selected from the group consisting of chemotherapeutic drug; toxin; immunological response modifier; enzyme; and radioisotope.
20. The method of claim 14 , wherein the cancer is resistant to therapeutic agents that cause cells to die by apoptosis or other methods.
21. A compound of claim 1 selected from the group consisting of:
trans-3-(2-Methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one;
trans-3-(1H-Indol-3-yl)-1-(2-pyridinyl)-2-propen-1-one;
trans-3-(1H-Indol-3-yl)-1-(3-pyridinyl)-2-propen-1-one;
trans-3-(1H-Indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one;
trans-3-(5-Methoxy-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one;
trans-3-(5-Phenylmethoxy-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one;
trans-3-(5-Hydroxy-1H-Indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one;
trans-3-(5-Methoxy-1H-indol-3-yl)-1-(3-pyridinyl)-2-propen-1-one;
trans-3-(5-Methoxy-1H-indol-3-yl)-1-(pyrazine)-2-propen-1-one;
trans-3-(5-Methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one;
trans-3-(5-Methoxy-1-methyl-Indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one;
trans-3-(5-Hydroxy-1H-Indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one;
trans-3-[5-((4-Methylbenzoate)methoxy)-1H-Indol-3-yl)]-1-(4-pyridinyl)-2-propen-1-one;
trans-3-[5-((4-Carboxyphenyl)-methoxy)-1H-Indol-3-yl)]-1-(4-pyridinyl)-2-propen-1-one;
and pharmaceutically acceptable salts, hydrates, and optical isomers thereof.
22. A compound of claim 21 , wherein the compound consists essentially of trans-3-(5-Methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one.
23. The method of claim 14 , wherein Ar is 4-pyridyl and the cancer is resistant to therapeutic agents that cause cells to die by apoptosis or other methods.