RNA photocleavage using texaphyrins

• US 5,714,328 A
• Filed: 06/07/1995
• Issued: 02/03/1998
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated), Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Sessler, Jonathan L., Magda, Darren
• Primary Examiner(s): Jones, W. Gary
• Assistant Examiner(s): REES, DIANE
• Application Number:
  US08/484,551
• Time in Patent Office: 972 Days
• Field of Search: 435/6, 435/5, 536/24.5, 514/44, 514/2, 424/9.362, 204/157.5, 604/4, 604/5
• US Class Current: 435/6.16
• CPC Class Codes: A61K 41/0042 Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Methods for photocleavage of a polymer of ribonucleic acid using a texaphyrin or a texaphyrin metal complex are provided. A preferred method of use is the site-specific cleavage of a polymer of ribonucleic acid and a preferred texaphyrin is a derivatized texaphyrin having binding specificity, in particular, a texaphyrin covalently coupled to a site-directing molecule, preferably an oligonucleotide. Possible substrates for cleavage include messenger, ribosomal, transfer, small nuclear, and small cytosolic ribonucleic acids, and RNA cofactors, thereby inactivating these ribonucleic acids and providing a multifaceted approach for treating benign or malignant cancer cells, or other undesired cells or tissues.

Claims

1. A method of light-induced cleavage of a polymer of ribonucleic acid, the method comprising:

contacting the polymer with a photosensitive texaphyrin; and

exposing the photosensitive texaphyrin to light for a time sufficient to cleave the polymer.

2. The method of claim 1 where the photosensitive texaphyrin has the structure:

##STR4## wherein M is H or a diamagnetic metal cation;

R₁ -R₄, R₇ and R₈ are independently hydrogen, halide, hydroxyl, alkyl, aryl, haloalkyl, nitro, formyl, acyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, saccharide, carboxy, carboxyalkyl, carboxyamidealkyl, a site-directing molecule, or a couple that is coupled to a site-directing molecule;

R₆ and R₉ are independently selected from the groups of R₁ -R₄, R₇ and R₈, with the proviso that the halide is other than iodide and the haloalkyl is other than iodoalkyl;

R₅ and R₁₀ -R₁₂ are independently hydrogen, alkyl, aryl, hydroxyalkyl, alkoxy, hydroxyalkoxy, carboxyalkyl, carboxyamidealkyl or a couple that is coupled to a saccharide, or to a site-directing molecule; and

n is an integer less than or equal to 5.

3. The method of claim 2 wherein the site-directing molecule is an oligonucleotide, an antibody, a hormone, a peptide having affinity for a biological receptor, or a sapphyrin molecule.

4. The method of claim 2 wherein at least one of R₁, R₂, R₃, R₇ and R₈ is a site-directing molecule, or a couple that is coupled to a site-directing molecule.

5. The method of claim 2 wherein at least one of R₁, R₂, R₃, R₇ and R₈ is an oligonucleotide, or a couple that is coupled to an oligonucleotide.

6. The method of claim 2 wherein R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, R₈ is a site-directing molecule, or a couple that is coupled to a site-directing molecule, and R₇ is H.

7. The method of claim 2 where R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, R₇ is O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃, and R₈ is a site-directing molecule, or a couple that is coupled to a site-directing molecule.

8. The method of claim 2 wherein R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, and R₇ and R₈ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃.

9. The method of claim 2 wherein R₁ -R₄, R₇, and R₈ are as in Table 1 for texaphyrins A1-A22.

10. The method of claim 2 wherein M is a diamagnetic metal cation and the diamagnetic metal cation is Lu(III), La(III), In(III), Y(III), Zn(II) or Cd(II).

11. The method of claim 2 wherein M is a diamagnetic metal cation and the diamagnetic metal cation is Lu(III).

12. The method of claim 1 wherein the light has a wavelength range of about 700 to 800 nanometers.

13. The method of claim 2 where R₁ is (CH₂)₂ CH₂ OH;

R₂ and R₃ are CH₂ CH₃ ;

R₄ is CH₃ ;

R₇ is OCH₃ ; and

R₈ is a site-directing molecule, or a couple that is coupled to a site-directing molecule.

14. The method of claim 7 where the site-directing molecule is an oligonucleotide.

15. The method of claim 13 where the site-directing molecule is an oligonucleotide.