Methods of regulating actin cytoskeletal rearrangement and intercellular gap formation

• US 8,809,303 B2
• Filed: 04/09/2009
• Issued: 08/19/2014
• Est. Priority Date: 04/09/2008
• Status: Expired due to Fees

• Current Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Original Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Egan, Thomas Michael
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US12/936,801
• Publication Number:
  US 20110053871A1
• Time in Patent Office: 1,958 Days
• Field of Search: 514/62
• US Class Current: 514/62
• CPC Class Codes: A61K 31/7008 Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
• CPC Class Codes: A61K 31/7028 Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Methods are described for reducing cytoskeletal rearrangement and intercellular gap formation by contacting cells with an aminoalkyl glucosaminide phosphate. In particular, the methods can be used to reduce actin cytoskeletal rearrangement and/or intracellular gap formation related to ischemic or ischemia-reperfusion events and to alleviate diseases or conditions related to increased actin cytoskeletal rearrangement.

Claims

1. A method of reducing actin cytoskeletal rearrangement or intercellular gap formation in a cell, the method comprising contacting the cell during cold ischemia with an effective amount of a compound of Formula (I):

2. The method of claim 1, wherein n is 1.

3. The method of claim 1, wherein X₁ and X₂ are each O.

4. The method of claim 1, wherein R₄ is —

C(═

O)OH.

5. The method of claim 1, wherein R₁, R₂, and R₃ are each C₂-C₇ acyl.

6. The method of claim 1, wherein the compound of Formula (I) is a compound wherein:

n is 1;

X₁ is O;

X₂ is O;

R₁, R₂ and R₃ are each —

C(═

O)(CH₂)₄CH₃;

R₄ is —

C(═

O)OH; and

R₅, R₆, and R₇ are each —

(CH₂)₁₀CH₃, or

a pharmaceutically acceptable salt thereof.

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

8. The method of claim 7, wherein the cell is an endothelial cell.

9. The method of claim 1, wherein contacting the cell occurs during cold ischemia in a cell in an extracorporeal tissue or organ or in a tissue or organ that is being transplanted from a tissue or organ donor into a transplant recipient, and reducing actin cytoskeletal rearrangement or intercellular gap formation comprises reducing actin cytoskeletal rearrangement or intercellular gap formation related to organ or tissue transplant.

10. A method of maintaining or preserving a transplantable extracorporeal tissue or organ by reducing actin cytoskeletal rearrangement and/or intercellular gap formation in one or more cells in the tissue or organ, the method comprising contacting the transplantable extracorporeal tissue or organ during cold ischemia with a supplementing solution comprising an effective amount of a compound of Formula (I):

11. The method of claim 10, wherein n is 1.

12. The method of claim 10, wherein X₁ and X₂ are each O.

13. The method of claim 10, wherein R₄ is —

C(═

O)OH.

14. The method of claim 10, wherein R₁, R₂, and R₃ are each C₂-C₇ acyl.

15. The method of claim 10, wherein the compound of Formula (I) is a compound wherein:

n is 1;

X₁ is O;

X₂ is O;

R₁, R₂ and R₃ are each —

C(═

O)(CH₂)₄CH₃;

R₄ is —

C(═

O)OH; and

R₅, R₆, and R₇ are each —

(CH₂)₁₀CH₃, or

a pharmaceutically acceptable salt thereof.