Synthetic drug molecules that mimic metalloenzymes

• US 5,202,317 A
• Filed: 09/13/1990
• Issued: 04/13/1993
• Est. Priority Date: 09/13/1990
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Bruice, Thomas C.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): GUPTA, YOGENDRA N
• Application Number:
  US07/582,626
• Time in Patent Office: 943 Days
• Field of Search: 514/185, 540/145
• US Class Current: 514/185
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings

Abstract

Synthetic enzymes that mimic the catalytic activity of naturally occurring enzymes by providing catalytic sites enclosed in cages that protect the sites from undesirable molecules and attract and permit entry of the relevant substrates are disclosed. Molecules that mimics the catalytic activity of superoxide dismutase and catalase, pharmaceutical compositions containing these molecules, and methods for using these compositions are also disclosed.

Claims

1. A synthetic catalyst for biological reactants which comprises:

(a) two quasi-planar π

-conjugated ring systems, each of which has an interfacial and extrafacial plane, and each of which is capable of chelating a transition metal ligand;

(b) two transition metal ligands such as iron, manganese, copper, or cobalt, each of which is chelated by one of the ring systems;

(c) at least two bridging units, each of which is covalently linked to the two ring systems, so that the ring systems are fixed to an interfacial plane separation in the range of about 4 to 7 angstroms; and

(d) two capping groups, each of which is situated on the extrafacial plane side of one of the ring systems, and each of which is attached to the ring systems through at least one direct or indirect covalent linkage, so that extrafacial access to the ring systems for naturally occurring biological molecules is barred,

wherein the ring systems are tetrapyrrole derivatives.

2. The catalyst of claim 1 wherein the tetrapyrrole derivatives are 5,10,15,20-tetrakis(phenyl)porphyrins.

3. The catalyst of claim 1 wherein the two transition metal ligands are selected from the group consisting of iron(III), manganese(III), copper(II) and combinations thereof.

4. The catalyst of claim 2 wherein the two transition metal ligands are selected from the group consisting of iron(III), manganese(III), copper(II) and combinations thereof.

5. The catalyst of claim 1 wherein the biological reactants are superoxide anion, hydroperoxide anion and hypochlorite anion.

6. The catalyst of claim 2 wherein the biological reactants are superoxide anion, hydroperoxide anion and hypochlorite anion.

7. The catalyst of claim 6 wherein the bridging units are covalently linked to the phenyl moieties of the ring systems.

8. The catalyst of claim 1 wherein the biological reactants are charged, and further comprising:

(e) one or more concentrating groups covalently linked to the bridging units, the concentrating groups possessing a charge opposing that of the biological reactants.

9. The catalyst of claim 8 wherein the tetrapyrrole derivatives are 5,10,15,20-tetrakis(phenyl)porphyrins.

10. The catalyst of claim 9 wherein the two transition metal ligands are selected from the group consisting of iron(III), manganese(III), copper(II) and combinations thereof.

11. The catalyst of claim 10 wherein the biological reactants are superoxide anion, hydroperoxide anion and hypochlorite anion.

12. The catalyst of claim 11 wherein the bridging units are covalently linked to the phenyl moieties of the ring systems.

13. The catalyst of claim 12 wherein the bridging units and concentrating groups together are --CH₂ --NR--CH₂ --, wherein R is a positively charged concentrating group.

14. The catalyst of claim 13 wherein the positively charged concentrating group is a guanido group.

15. The catalyst of claim 14 having exactly four bridging units and concentrating groups, each bridging unit being covalently linked to a different phenyl moiety on the two ring systems.

16. The catalyst of claim 15 wherein the two transition metal ligands are iron(III).

17. The catalyst of claim 1 wherein the two capping groups are selected from the group consisting of aryl, cycloalkyl and aromatic heterocycles, and wherein each capping group is attached to a different ring system through at least one --(CH₂)_n -- linkage, wherein n is an integer between 2 and 10.

18. The catalyst of claim 16 wherein the two capping groups are selected from the group consisting of phenyl, aryl, cycloalkyl and aromatic heterocycles, and wherein each capping group is attached to a different ring system through at least one --(CH₂)_n -- linkage, wherein n is an integer between 2 and 10.

19. The catalyst of claim 18 wherein the two capping groups are phenyl groups, each phenyl group being attached to a different ring system through four --(CH₂)₅ -- linkages, wherein each linkage is attached to a different phenyl moiety on each ring system.

20. A pharmaceutical composition for the treatment of reactive oxidant tissue damage comprising an effective reactive oxidant-reducing amount of the catalyst of claim 1 and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition for the treatment of reactive oxidant tissue damage comprising an effective reactive oxidant-reducing amount of the catalyst of claim 8 and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition for the treatment of reactive oxidant tissue damage comprising an effective reactive oxidant-reducing amount of the catalyst of claim 11 and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition for the treatment of reactive oxidant tissue damage comprising an effective reactive oxidant-reducing amount of the catalyst of claim 19 and a pharmaceutically acceptable carrier.

24. A method for the prevention and treatment of reactive oxidant tissue damage comprising administering to a patient in need of such treatment an effective amount of the composition of claim 20.

25. A method for the prevention and treatment of reactive oxidant tissue damage comprising administering to a patient in need of such treatment an effective amount of the composition of claim 21.

26. A method for the prevention and treatment of reactive oxidant tissue damage comprising administering to a patient in need of such treatment an effective amount of the composition of claim 22.

27. A method for the prevention and treatment of reactive oxidant tissue damage comprising administering to a patient in need of such treatment an effective amount of the composition of claim 23.

28. A method for the reduction of the level of cancer-causing oxygen species in a patient comprising administering to the patient an effective amount of the composition of claim 20.

29. A method for the reduction of the level of cancer-causing oxygen species in a patient comprising administering to the patient an effective amount of the composition of claim 21.

30. A method for the reduction of the level of cancer-causing oxygen species in a patient comprising administering to the patient an effective amount of the composition of claim 22.

31. A method for the reduction of the level of cancer-causing oxygen species in a patient comprising administering to the patient an effective amount of the composition of claim 23.