Polyenolic zinc-binding agents (pezbins) actively promote inactivation of cancer stem cells and potentiate cytotoxic anti-tumor drug substances

Patent metadata

Field	Value
Publication number	US-9675576-B2
Application number	US-201514950033-A
Country	US
Kind code	B2
Filing date	Nov 24, 2015
Priority date	Jun 29, 2012
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

The present invention provides a method of inhibiting the growth of or promoting differentiation and destruction of cancer stem cells (CSCs) comprising contacting the cancer stem cells with a compound having the structure:

or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A method of inhibiting the growth of or promoting differentiation of cancer stem cells (CSCs) or down-regulating cancer stem cell-relevant transcription factors in a patient in need thereof comprising contacting the cancer stem cells in the patient with a compound having the structure:

wherein R 14 is C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, —OR n , —NR 16 R 17 , or

wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-40 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 18 , R 19 , R 21 , and R 22 are each independently H, halogen, —NO 2 , —CN, —NR 23 R 24 , —SR 23 , —SO 2 R 23 , —CO 2 R 23 , —OR 25 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 23 , R 24 , and R 25 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;

R 20 is halogen, —NO 2 , —CN, —NR 26 R 27 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 26 and R 27 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and

wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and
or a salt thereof, so as to thereby inhibit the growth of or promote differentiation of the cancer stem cells (CSCs) or down-regulate cancer stem cell-relevant transcription factors.

2. The method of claim 1 , further comprising contacting the cancer stem cell with a chemotherapeutic agent.

3. The method of claim 1 , wherein the cancer stem cell-relevant transcription factors are at least five (5) transcription factors selected from the group consisting of CDX2, DLX2, EGR3, FOXP3, GLI2, HOXA2, HOXA7, HOXB3, HOXB8, HOXC10, HOXC9, HOXC6, HOXC4, HOXC5, IRX4, JUN, KLF2, NFATC1, NR2F2, PITX3, POU5F1, RUNX1, WT1, c-MYC, and SOX-2.

4. A method of inhibiting the growth of a tumor comprising cancer stem cells (CSCs) in a patient diagnosed to be suffering from cancer by contacting the tumor in the patient with a compound having the structure:

wherein R 14 is C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, —OR 15 , —NR 16 R 17 , or

wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 18 , R 19 , R 21 , and R 22 are each independently H, halogen, —NO 2 , —CN, —NR 23 R 24 , —SR 23 , —SO 2 R 23 , —CO 2 R 23 , —OR 25 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 23 , R 24 , and R 25 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;

R 20 is halogen, —NO 2 , —CN, —NR 26 R 27 , CF 3 , C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 26 and R 27 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl; and

wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and
or a salt thereof, so as to thereby inhibit the growth of the tumor comprising cancer stem cells (CSCs).

5. The method of claim 4 , wherein the compound inhibits the growth of cancer stem cells, promotes the differentiation of cancer stem cells or inhibits cancer stem cell-relevant transcription factors.

6. The method of claim 4 , further comprising contacting the tumor with a chemotherapeutic agent.

7. The method of claim 6 , wherein the growth of cancer stem cells is not inhibited by, or the differentiation of cancer stem cells is not promoted by, or the cancer stem cell-relevant transcription factors are not inhibited by, the chemotherapeutic agent.

8. The method of claim 6 , wherein the tumor is resistant to a chemotherapeutic agent due to the presence of cancer stem cells in the tumor.

9. The method of claim 2 , wherein the chemotherapeutic agent is SBT-1214, abraxane, afinitor, erlotinib hydrochloride, gemcitabine hydrochloride, irinotecan hydrochloride, mitomycin C, sunitinib malate, taxol, taxotere, paclitaxel, cis-platin, or oxaliplatin.

10. The method of claim 6 , wherein the chemotherapeutic agent is SBT-1214, abraxane, afinitor, erlotinib hydrochloride, gemcitabine hydrochloride, irinotecan hydrochloride, mitomycin C, sunitinib malate, taxol, taxotere, paclitaxel, cis-platin, or oxaliplatin.

11. A method of treating a patient diagnosed to be suffering from cancer comprising administering to the patient a compound having the structure:

wherein R 14 is C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, —OR n , —NR 16 R 17 , or

wherein R 15 is H, C 3-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl;
R 16 and R 17 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
R 18 , R 19 , R 21 , and R 22 are each independently H, halogen, —NO 2 , —CN, —NR 23 R 24 , —SR 23 , —SO 2 R 23 , —CO 2 R 23 , —OR 25 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 23 , R 24 , and R 25 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;

R 20 is halogen, —NO 2 , —CN, —NR 26 R 27 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 26 and R 27 are each, independently, H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently, H, halogen, —NO 2 , —CN, —NR 28 R 29 , —SR 28 , —SO 2 R 28 , —OR 28 , —CO 2 R 28 , CF 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R 28 and R 29 are each, H, CF 3 , C 1-10 alkyl, C 2-10 alkenyl, or C 2-10

Assignees

• Univ New York State Res Found
• Chem-Master Int Inc

Inventors

• Golub Lorne M
• Johnson Francis
• Botchkina Galina I
• Ojima Iwao

Classifications

• A61K31/216 Primary

  of acids having aromatic rings, e.g. benactizyne, clofibrate · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/136

  having the amino group directly attached to the aromatic ring, e.g. benzeneamine · CPC title