Inhibition of respiratory complex III by ligands that interact with a regulatory switch

Patent metadata

Field	Value
Publication number	US-11058645-B2
Application number	US-201916531511-A
Country	US
Kind code	B2
Filing date	Aug 5, 2019
Priority date	Feb 10, 2017
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

The present invention provides methods for inhibiting respiratory complex III in a cell. The present invention also provides methods for treating cancer in a subject.

First claim

What is claimed is:

1. A method of inhibiting respiratory complex III in a cell, comprising:
contacting the cell with a compound having a structure selected from the group consisting of:

wherein
each R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylhydroxy, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-12 aryl, halogen, hydroxyl, oxide, —CN, —NH 2 , —NO 2 , and —C(O)—C 1-6 alkyl, and —C(O)O − ;
the subscripts m and n are each independently integers from 0 to 5;
the subscript p is an integer from 0 to 4;
the subscripts q and u are each independently integers from 0 to 2; and
the subscript w is an integer from 0 to 3;

such that the compound binds to respiratory complex III, thereby inhibiting respiratory complex III.

2. The method of claim 1 , wherein the compound has the structure of Formula I:

wherein
each R 1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, —NO 2 , and —C(O)—C 1-6 alkyl;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, hydroxyl, —CN, —NH 2 , —C(O)O—C 1-6 alkyl, and —C(O)O − ,
each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, and oxide;
each R 4 is independently selected from the group consisting of hydrogen and C 1-6 alkyl;
the subscripts m and n are each independently integers from 0 to 5;
the subscript p is an integer from 0 to 4;
and the subscript q is an integer from 0 to 2.

3. The method of claim 1 , wherein the compound has the structure of Formula II:

wherein
each R 1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, —NO 2 , and —C(O)—C 1-6 alkyl;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, hydroxyl, —CN, —NH 2 , —C(O)O—C 1-6 alkyl, and —C(O)O − , and
the subscripts m and n are each independently integers from 0 to 5.

4. The method of claim 1 , wherein the compound has the structure of Formula XI:

wherein
each R 1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, —NO 2 , and —C(O)—C 1-6 alkyl;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, hydroxyl, —CN, —NH 2 , —C(O)O—C 1-6 alkyl, and —C(O)O − ,
the subscripts m and n are each independently integers from 0 to 5; and
the subscript w is an integer from 0 to 3.

5. The method of claim 1 , wherein the compound has the structure of Formula XII:

wherein
each R 1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl, —NO 2 , and —C(O)—C 1-6 alkyl;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-12 aryl, hydroxyl, —CN, —NH 2 , —C(O)O—C 1-6 alkyl, and —C(O)O − ,
each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, and oxide;
each R 4 is independently selected from the group consisting of hydrogen and C 1-6 alkyl;
each R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxyl, and C(O)O − ;
the subscripts m and n are each independently integers from 0 to 5;
the subscript p is an integer from 0 to 4; and
the subscripts q and u are each independently integers from 0 to 2.

6. The method of claim 1 , wherein the compound is selected from group consisting of

7. The method of claim 1 , wherein the cell is a cancer cell.

8. The method of claim 7 , wherein the cancer cell is in a subject.

9. The method of claim 8 , further comprising administering to the subject an amount of the compound effective to inhibit respiratory complex III in the cancer cell.

10. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound having a structure selected from the group consisting of:

wherein
each R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylhydroxy, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-12 aryl, halogen, hydroxyl, oxide, —CN, —NH 2 , —NO 2 , and —C(O)—C 1-6 alkyl, and C(O)O − ;
the subscripts m and n are each independently integers from 0 to 5;
the subscript p is an integer from 0 to 4;
the subscripts q and u are each independently integers from 0 to 2; and
the subscript w is an integer from 0 to 3.

Assignees

• Univ California

Inventors

• Hagras Muhammad
• Stuchebrukhov Alexei

Classifications

• A61K31/352

  condensed with carbocyclic rings, e.g. methantheline  {(cannabinoids A61K31/658)} · CPC title

• A61K31/192

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• A61K31/05

  Phenols {(cannabinoids A61K31/658)} · CPC title

• C07D243/24

  Oxygen atoms · CPC title

• C07D493/04

  Ortho-condensed systems · CPC title