Methods of treatment using modulators of SIRT2
The instant application describes novel compounds that modulate (in particular, inhibit) Sirt 2 , with structures according to Formulas (1) and (2) provided herein. The invention is also directed to pharmaceutical compositions thereof, methods of treatment (i.e., cancer and neurodegenerative disease) by administration of the modulating compounds, assay methods for finding modulators of Sirt 2 , and kits for practicing the assay method.
1. A compound that modulates Sirt2 activity having the following chemical structure:
wherein R 1 is a hydrocarbon group having at least five carbon atoms connected by carbon-carbon bonds, wherein said hydrocarbon group optionally includes one heteroatom group selected from —O—, —NR 5 —, and —S— that interrupts a carbon-carbon bond of said hydrocarbon group, and wherein one or more hydrogen atoms in said hydrocarbon group are optionally replaced with fluoro atoms, wherein R 5 is a hydrogen atom or a hydrocarbon group;
R 2 is selected from a hydrogen atom or a hydrocarbon group;
R 6 and R 7 are independently selected from hydrogen atom, unsubstituted hydrocarbon groups having up to six carbon atoms, alkoxy groups —OR, amide groups —NR′C(O)R or —C(O)NR′R, ketone groups —C(O)R, ester groups —C(O)OR or —OC(O)R, carbamate groups —OC(O)NR′R or —NR′C(O)OR, and urea groups —NR′C(O)NR, wherein R is a hydrocarbon group having up to six carbon atoms, and R′ is a hydrogen atom or a hydrocarbon group having up to six carbon atoms;
X 1 , X 2 , and X 3 are independently selected from —(CH 2 ) n —, —NR 5 —, —O—, —S—, or a bond, wherein n represents 1, 2, or 3, and at least one of X 1 , X 2 , and X 3 is a —CH 2 —group; and
Y 1 and Y 2 are independently selected from —O—, —NR 5 —, and —S— groups.
2. The compound of claim 1 , wherein said hydrocarbon group for R 1 has at least five carbon atoms connected by carbon-carbon bonds in the absence of heteroatom interruption, except that one or more hydrogen atoms are optionally replaced with fluoro atoms.
3. The compound of claim 1 , wherein said hydrocarbon group for R 1 has at least six carbon atoms.
4. The compound of claim 1 , wherein said hydrocarbon group for R 1 has at least seven carbon atoms.
5. The compound of claim 1 , wherein said hydrocarbon group for R 1 has at least eight carbon atoms.
6. The compound of claim 1 , wherein said hydrocarbon group for R 1 has up to twenty carbon atoms.
7. The compound of claim 1 , wherein each of X 1 , X 2 , and X 3 is —(CH 2 ) n —, wherein n is independently 1, 2, or 3.
8. The compound of claim 1 , wherein each of X 1 , X 2 , and X 3 is —CH 2 —.
9. The compound of claim 1 , wherein Y 1 is an —O— atom.
10. The compound of claim 1 , wherein Y 2 is an —NR 5 — group.
11. The compound of claim 1 , wherein Y 1 is an —O— atom and Y 2 is an —NR 5 — group.
12. The compound of claim 1 , wherein R 6 and R 7 are independently selected from hydrogen atom, unsubstituted hydrocarbon groups having up to three carbon atoms, alkoxy groups —OR, amide groups —NR′C(O)R or —C(O)NR′R, ketone groups —C(O)R, ester groups —C(O)OR or —OC(O)R, carbamate groups —OC(O)NR′R or —NR′C(O)OR, and urea groups —NR′C(O)NR, wherein R is a hydrocarbon group having up to three carbon atoms, and R′ is a hydrogen atom or a hydrocarbon group having up to three carbon atoms.
13. A method for treating a subject suffering from a neurodegenerative disorder, the method comprising administering to said subject a modulator of Sirt2 according to claim 1 in a pharmaceutically effective amount for treating said neurodegenerative disorder, wherein said neurodegenerative disorder is selected from Parkinson's Disease, Huntington's Disease, and Alzheimer's Disease.
14. The method of claim 13 , wherein said neurodegenerative disorder is Parkinson's Disease.
15. The method of claim 13 , wherein said modulator of Sirt2 is an inhibitor of Sirt2.
16. The method of claim 15 , wherein said inhibitor of Sirt2 is a selective inhibitor of Sirt2.
17. The method of claim 13 , wherein the hydrocarbon group for R 1 has at least five carbon atoms connected by carbon-carbon bonds in the absence of heteroatom interruption, except that one or more hydrogen atoms are optionally replaced with fluoro atoms.
18. A method for treating a subject suffering from breast cancer, the method comprising administering to said subject a modulator of Sirt2 in a pharmaceutically effective amount for treating said breast cancer, the modulator of Sirt2 having the following chemical structure:
wherein R 1 is a hydrocarbon group having at least five carbon atoms connected by carbon-carbon bonds, wherein said hydrocarbon group optionally includes one heteroatom group selected from —O—, —NR 5— , and —S— that interrupts a carbon-carbon bond of said hydrocarbon group, and wherein one or more hydrogen atoms in said hydrocarbon group are optionally replaced with fluoro atoms, wherein R 5 is a hydrogen atom or a hydrocarbon group;
R 2 is selected from a hydrogen atom or a hydrocarbon group;
R 3 and R 4 are independently selected from hydrogen atom and hydrocarbon groups R, wherein said hydrocarbon groups R are optionally substituted with one or more heteroatoms; and
X 1 , X 2 , and X 3 are independently selected from —(CH 2 ) n —, —NR 5 —, —O—, —S—, or a bond, wherein n represents 1, 2, or 3, and at least one of X 1 , X 2 , and X 3 is a —CH 2 — group.
19. The method of claim 18 , wherein the hydrocarbon group for R 1 has at least five carbon atoms connected by carbon-carbon bonds in the absence of heteroatom interruption, except that one or more hydrogen atoms are optionally replaced with fluoro atoms.
20. The method of claim 18 , wherein said modulator of Sirt2 is an inhibitor of Sirt2.
21. The method of claim 20 , wherein said inhibitor of Sirt2 is a selective inhibitor of Sirt2.
22. The method of claim 18 , wherein said breast cancer is triple negative breast cancer.
23. The method of claim 18 , wherein at least one of R 3 and R 4 is comprised of at least one amino acid residue.
24. The method of claim 18 , wherein at least one of R 3 and R 4 is comprised of a monocyclic unsaturated ring.
25. The method of claim 18 , wherein each of R 3 and R 4 is comprised of a monocyclic unsaturated ring.
26. The method of claim 18 , wherein said modulator of Sirt2 has the following chemical structure:
wherein R 1 is a hydrocarbon group having at least five carbon atoms connected by carbon-carbon bonds, wherein said hydrocarbon group optionally includes one heteroatom group selected from —O—, —NR 5 —, and —S— that interrupts a carbon-carbon bond of said hydrocarbon group, and wherein one or more hydrogen atoms in said hydrocarbon group are optionally replaced with fluoro atoms, wherein R 5 is a hydrogen atom or a hydrocarbon group;
R 2 is selected from a hydrogen atom or a hydrocarbon group;
R 6 and R 7 are independently selected from hydrogen atom, unsubstituted hydrocarbon groups having up to six carbon atoms, alkoxy groups —OR, amide groups —NR′C(O)R or —C(O)NR′R, ketone groups —C(O)R, ester groups —C(O)OR or —OC(O)R, carbamate groups —OC(O)NR′R or —NR′C(O)OR, and urea groups —NR′C(O)NR, wherein R is a hydrocarbon group having up to six carbon atoms, and R′ is a hydrogen atom or a hydrocarbon group having up to six carbon atoms;
X 1 , X 2 , and X 3 are independently selected from —(CH 2 ) n —, —NR 5 —, —O—, —S—, or a bond, wherein n represents 1, 2, or 3, and at least one of X 1 , X 2 , and X 3 is a —CH 2 — group; and
Y 1 and Y 2 are independently selected from —O—, —NR 5 —, and —S— groups.