Glutathione-cleavable prodrug and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10023551-B2
Application number	US-201615573183-A
Country	US
Kind code	B2
Filing date	May 12, 2016
Priority date	May 12, 2015
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

A glutathione-cleavable prodrug is provided herein, as well as methods for its use in treating cancer, including triple negative breast cancer. The prodrug can be cleaved by glutathione under physiological conditions to generate a biologically active agent. The compound described herein is advantageous as the compound is fluorescent and can therefore be monitored within a subject.

First claim

What is claimed is:

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof.

2. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. A kit comprising a compound of claim 1 .

4. A method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound of claim 1 , wherein the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, colon cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, renal cancer, skin cancer, or testicular cancer.

5. The method of claim 4 , wherein the cancer is breast cancer.

6. The method of claim 5 , wherein the breast cancer is triple negative breast cancer.

7. A method of inhibiting angiogenesis in a subject, comprising administering to the subject an effective amount of a compound of claim 1 .

8. The method of claim 7 , wherein the subject has cancer.

9. The method of claim 8 , wherein the cancer is triple negative breast cancer.

10. The method of claim 8 , wherein the cancer overexpresses glutathione.

11. A method of inhibiting tubulin polymerization in a cell, comprising contacting the cell with an effective amount of a compound of claim 1 .

12. The method of claim 11 , wherein the cell is a cancer cell.

13. The method of claim 12 , wherein the cancer cell is a triple negative breast cancer cell.

14. The method of claim 11 , wherein the cell is a cell that overexpresses glutathione.

15. A method of delivering combretastatin A-4 to a cell, comprising contacting a cell comprising glutathione with a compound of claim 1 , wherein the glutathione cleaves the compound to form combretastatin A-4.

16. The method of claim 15 , wherein the cell is a cancer cell.

17. The method of claim 16 , wherein the cancer cell is a triple negative breast cancer cell.

18. The method of claim 15 , wherein the cell is a cell that overexpresses glutathione.

19. The method of claim 11 , wherein the contacting is performed in vivo.

20. The method of claim 11 , wherein the contacting is performed in vitro.

21. A method of imaging a glutathione containing cell or population of cells in a subject, comprising:
administering to the subject a compound of claim 1 ; and
detecting fluorescence in the subject, wherein fluorescence indicates a glutathione containing cell or population of cells.

22. The method of claim 21 , wherein the glutathione containing cell or population of cells is a cancer cell or cancerous population of cells.

Assignees

• Univ Georgetown

Inventors

• Brown Milton L
• Kong Yali
• Smith Jacqueline
• Wang Kan
• Hou Shujie

Classifications

• A61K49/0021

  the fluorescent group being a small organic molecule · CPC title

• C07C69/003

  Esters of saturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D311/18

  substituted otherwise than in position 3 or 7 · CPC title

• G01N21/64

  Fluorescence; Phosphorescence · CPC title