Texaphyrins and uses thereof

• US 5,567,687 A
• Filed: 09/21/1994
• Issued: 10/22/1996
• Est. Priority Date: 03/06/1989
• Status: Expired due to Term

• Current Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), University of Texas System
• Inventors: Jansen, Petra L., Sessler, Jonathan L., Magda, Darren, Mody, Tarak D., Iverson, Brent, Wright, Meredith, Hemmi, Gregory W.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/310,501
• Time in Patent Office: 762 Days
• Field of Search: 514/44, 536/23.1, 536/24.2, 204/157.68
• US Class Current: 514/44.00R
• 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 41/0076 PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
• CPC Class Codes: A61K 47/546 Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/106 the complex-forming compound being cyclic, e.g. DOTA
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 51/0485 Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
• CPC Class Codes: A61L 2/0011 using physical methods
• CPC Class Codes: B01J 2531/025 Ligands with a porphyrin ring system or analogues thereof, e.g. phthalocyanines, corroles
• CPC Class Codes: B01J 2531/26 Zinc
• CPC Class Codes: B01J 2531/27 Cadmium
• CPC Class Codes: B01J 2531/33 Indium
• CPC Class Codes: B01J 2531/37 Lanthanum
• CPC Class Codes: B01J 2531/38 Lanthanides other than lanthanum
• CPC Class Codes: B01J 31/0201 Oxygen-containing compounds
• CPC Class Codes: B01J 31/1658 immobilised by covalent linkages, i.e. pendant complexes with optional linking groups, e.g. on Wang or Merrifield resins
• CPC Class Codes: B01J 31/1815 with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/113 : Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/15 : Nucleic acids forming more than 2 strands, e.g. TFOs
• CPC Class Codes: C12N 2310/321 : 2'-O-R Modification
• CPC Class Codes: C12N 2310/3511 : intercalating or cleaving agent
• CPC Class Codes: C12N 2310/3521 : Methyl

Abstract

A texaphyrin having substituents containing ethoxy groups, methods for using texaphyrins in photodynamic therapy, and cleavage of a polymer of deoxyribonucleic acid are disclosed. The in vivo treatment of tumors and atheroma is demonstrated using Lu(III)texaphyrin complexes. A preferred method of use is the site-specific cleavage of a polymer of deoxyribonucleic 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.

Claims

1. A method of light-induced cleavage of a polymer of deoxyribonucleic 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 wherein the exposing step is carried out in the presence of oxygen.

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

##STR4## where;

M is H or a diamagnetic metal cation;

R₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, saccharide, carboxyalkyl, carboxyamidealkyl, a site-directing molecule or a couple to a site-directing molecule; and

N is an integer less than or equal to 2.

4. The method of claim 3 wherein at least one of R₁, R₂, R₃, R₄, R₅ and R₆ is a site-directing molecule or a couple to a site-directing molecule.

5. The method of claim 4 wherein the site-directing molecule is an oligonucleotide.

6. The method of claim 5 wherein the oligonucleotide is a 2'"'"'-O-alkylated ribonucleotide.

7. The method of claim 3 wherein one of R₃, R₅, and R₆ is an oligonucleotide or a couple to an oligonucleotide.

8. The method of claim 3 wherein R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, R₅ is a site-directing molecule or a couple to a site-directing molecule and R₆ is H.

9. The method of claim 3 where R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, R₅ is O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃, and R₆ is a site-directing molecule or a couple to a site-directing molecule.

10. The method of claim 3 wherein R₁ is (CH₂)₂ CH₂ OH, R₂ and R₃ are CH₂ CH₃, R₄ is CH₃, and R₅ and R₆ are O(CH₂ CH₂ O)₂ CH₂ CH₂ OCH₃.

11. The method of claim 3 wherein R₁ -R₆ are as in Table 1 for texaphyrins A1-A22.

12. The method of claim 3 wherein M is a diamagnetic metal cation and the diamagnetic metal is Lu(III), La(III), In(III), Zn(II) or Cd(II).

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