Multi-mechanistic chemical cleavage using certain metal complexes

• US 5,798,491 A
• Filed: 06/02/1995
• Issued: 08/25/1998
• Est. Priority Date: 06/09/1993
• Status: Expired due to Fees

• 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), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Sessler, Jonathan L., Magda, Darren
• Primary Examiner(s): Tsang, Cecelia J.
• Assistant Examiner(s): DELACROIX MUIRHEI, CYBILLE
• Application Number:
  US08/458,347
• Time in Patent Office: 1,180 Days
• Field of Search: 204/157.15, 204/157.68, 435/91.1
• US Class Current: 204/157.15
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• 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: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B01J 2531/025 Ligands with a porphyrin ring system or analogues thereof, e.g. phthalocyanines, corroles
• CPC Class Codes: B01J 2531/36 Yttrium
• 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
• CPC Class Codes: C12N 2310/3527 Other alkyl chain

Abstract

The invention is directed to a particular class of metal complexes, specifically certain texaphyrin metal complexes, which both hydrolyze and photocleave RNA, and which also both hydrolyze RNA and photocleave DNA.

In one embodiment, the present invention is directed to a method for both hydrolyzing and photocleaving a polymer of ribonucleic acid, the method comprising the steps of contacting the polymer of ribonucleic acid with a texaphyrin metal complex exhibiting catalytic activity for both hydrolysis and photocleavage of ribonucleic acid polymers, incubating the polymer and the metal complex under conditions and for a time sufficient to hydrolyze the phosphate ester bond of the polymer, and exposing the texaphyrin metal complex to light for a time sufficient to photocleave the polymer.

In another embodiment of the present invention, the invention is directed to a method for both hydrolyzing a polymer of ribonucleic acid and photocleaving a polymer of deoxyribonucleic acid, the method comprising the steps of contacting a mixture of the ribonucleic acid polymer and the deoxyribonucleic acid polymer with a texaphyrin metal complex exhibiting catalytic activity for both hydrolysis of ribonucleic acid polymers and photocleavage of deoxyribonucleic acid polymers, incubating the polymer mixture and the metal complex under conditions and for a time sufficient to hydrolyze the phosphate ester bond of the ribonucleic acid polymer, and exposing the texaphyrin metal complex to light for a time sufficient to photocleave the deoxyribonucleic acid polymer.

Claims

1. A method of both hydrolyzing and photocleaving a polymer of ribonucleic acid, the method comprising:

contacting the polymer of ribonucleic acid with a texaphyrin metal complex that exhibits catalytic activity for both hydrolysis and photocleavage of ribonucleic acid polymers,

incubating the polymer of ribonucleic acid and the metal complex under conditions and for a time sufficient to hydrolyze the phosphate ester bond of the polymer, and

exposing the texaphyrin metal complex to light for a time sufficient to photocleave the polymer.

2. The method of claim 1 wherein the texaphyrin metal complex is a texaphyrin-diamagnetic metal complex.

3. The method of claim 1 wherein the texaphyrin metal complex is a yttrium-texaphyrin complex.

4. The method of claim 1 wherein the light has a wavelength range of about 700-800 nm.

5. The method of claim 1 wherein the step of exposing the texaphyrin metal complex to light is carried out in the presence of oxygen.

6. The method of claim 1 wherein the texaphyrin metal complex has the formula:

##STR5## wherein, M is a divalent metal cation or a trivalent metal cation exhibiting catalytic activity for both hydrolysis and photocleavage of RNA polymers;

R₁ -R₄, R₇ and R₈ are independently hydrogen, halide, hydroxyl, alkyl, alkenyl, alkynyl, aryl, haloalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, saccharide, carboxy, carboxyalkyl, carboxyamide, carboxyamidealkyl, amino, aminoalkyl, a site-directing molecule, a catalytic group, or a couple to a site-directing molecule or to a catalytic group;

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, alkenyl, alkynyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, carboxyalkyl, carboxyamide, carboxyamidealkyl, amino, aminoalkyl, or a couple to a saccharide, to a site-directing molecule or to a catalytic group; and

Z is an integer value less than or equal to 5.

7. The method of claim 6 wherein M is yttrium(III).

8. The method of claim 6 wherein at least one of R₁ -R₁₂ is a site-directing molecule, a catalytic group, a couple to a site-directing molecule or a couple to a catalytic group.

9. The method of claim 8 wherein the catalytic group is imidazole, guanidine, an amino acid, an amino acid derivative, a polyamino acid, an amine-substituted saccharide or a texaphyrin metal complex.

10. The method of claim 8 wherein the site-directing molecule is an oligonucleotide, a hormone, an antibody, a peptide having affinity for a biological receptor, or a sapphyrin molecule.

11. The method of claim 6 wherein at least one of R₁ -R₁₂ is a site-directing molecule, and the site-directing molecule is an oligonucleotide, which oligonucleotide has binding affinity for RNA.

12. The method of claim 11 wherein the oligonucleotide is a derivatized oligonucleotide or an oligonucleotide analog.

13. The method of claim 12 wherein the derivatized oligonucleotide is selected from the group consisting of methylphosphonates, phosphotriesters, phosphorothioates, and phosphoramidates.

14. The method of claim 12 wherein the derivatized oligonucleotide is 2'"'"'-O-alkyl oligoribonucleotide.

15. The method of claim 11 wherein the oligonucleotide is an antisense oligonucleotide.

16. A method of both hydrolyzing a polymer of ribonucleic acid and photocleaving a polymer of deoxyribonucleic acid, the method comprising:

contacting a mixture of the ribonucleic acid polymer and the deoxyribonucleic acid polymer with a texaphyrin metal complex that exhibits catalytic activity for both hydrolysis of ribonucleic acid polymers and photocleavage of deoxyribonucleic acid polymers,

incubating the polymer mixture and the metal complex under conditions and for a time sufficient to hydrolyze the phosphate ester bond of the ribonucleic acid polymer, and

exposing the texaphyrin metal complex to light for a time sufficient to photocleave the deoxyribonucleic acid polymer

wherein the metal is yttrium(III) or dysprosium(III).

17. The method of claim 16 wherein the light has a wavelength range of about 700-800 nm.

18. The method of claim 16 wherein the step of exposing the texaphyrin metal complex to light is carried out in the presence of oxygen.

19. The method of claim 16 wherein the texaphyrin metal complex has the formula:

##STR6## wherein, M is yttrium(III) or dysprosium(III);

R₁ -R₄, R₇ and R₈ are independently hydrogen, halide, hydroxyl, alkyl, alkenyl, alkynyl, aryl, haloalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, saccharide, carboxy, carboxyalkyl, carboxyamide, carboxyamidealkyl, amino, aminoalkyl, a site-directing molecule, a catalytic group, or a couple to a site-directing molecule or to a catalytic group;

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, alkenyl, alkynyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, carboxyalkyl, carboxyamide, carboxyamidealkyl, amino, aminoalkyl, or a couple to a saccharide, to a site-directing molecule or to a catalytic group; and

Z is an integer value less than or equal to 5.

20. The method of claim 19 wherein M is yttrium(III).

21. The method of claim 19 wherein at least one of R₁ -R₁₂ is a site-directing molecule, a catalytic group, a couple to a site-directing molecule or a couple to a catalytic group.

22. The method of claim 21 wherein the catalytic group is imidazole, guanidine, an amino acid, an amino acid derivative, a polyamino acid, an amine-substituted saccharide or a texaphyrin metal complex.

23. The method of claim 21 wherein the site-directing molecule is an oligonucleotide, a hormone, an antibody, a peptide having affinity for a biological receptor, or a sapphyrin molecule.

24. The method of claim 23 wherein the oligonucleotide is a derivatized oligonucleotide or an oligonucleotide analog.

25. The method of claim 24 wherein the derivatized oligonucleotide is selected from the group consisting of methylphosphonates, phosphotriesters, phosphorothioates, and phosphoramidates.

26. The method of claim 24 wherein the derivatized oligonucleotide is 2'"'"'-O-alkyl oligoribonucleotide.

27. The method of claim 23 wherein the oligonucleotide is an antisense oligonucleotide.