Site-specific chiral ruthenium (II) and cobalt (III) antitumor agents

• US 4,699,978 A
• Filed: 01/18/1985
• Issued: 10/13/1987
• Est. Priority Date: 01/18/1985
• Status: Expired due to Term

• Current Assignee: Columbia University
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Barton, Jacqueline K.
• Primary Examiner(s): Kepplinger, Esther M.
• Assistant Examiner(s): Jay, Jeremy M.
• Application Number:
  US06/693,019
• Time in Patent Office: 998 Days
• Field of Search: 424/1.1, 424/9, 424/131, 424/149, 546/4, 546/10, 546/88, 556/136, 556/138, 536/22, 536/27, 435/6, 935/77, 935/78, 204/157.71, 204/157.72
• US Class Current: 536/24.3
• CPC Class Codes: C07F 15/0053 without a metal-carbon linkage
• CPC Class Codes: C07F 15/065 without a metal-carbon linkage
• CPC Class Codes: C12Q 1/68 involving nucleic acids
• CPC Class Codes: C12Q 1/6816 characterised by the detection means C12Q1/6804 takes precedence

Abstract

This invention concerns a coordination complex of the formula (R)₂ --M--(Y)₂ wherein M comprises a suitable transition metal, e.g. cobalt or ruthenium, R comprises 1,10-phenanthroline or a substituted derivative thereof, Y comprises a labile ligand, e.g. chloride, tartrate, malonate or ascorbate ion and R and Y are bonded to M by coordination bonds.

A complex of this invention may be used for covalently labeling DNA with a complex of the formula (R)₂ --M, wherein R and M are as previously defined. A complex of this invention which contains cobalt may also be used in a method for nicking DNA by effecting single-stranded scission of at least one phosphodiester bond of the DNA with ultraviolet radiation.

A complex of this invention is further useful in a method for killing tumor cells. A pharmaceutical composition for the treatment of tumor cells in a subject may be prepared containing an effective anti-tumor amount of a complex of this invention and a pharmaceutically acceptable carrier. Such a composition may be used for treating a subject afflicted with tumor cells so as to cause regression of the tumor cells.

Claims

1. A method for selectively nicking B-DNA or Z-DNA present within DNA by effecting breakage of at least one phosphodiester bond within the B-DNA or Z-DNA which comprises contacting the B-DNA or Z-DNA with a coordination complex of the formula (R)₂ --Co(III)--(Y)₂, wherein R comprises 1,10-phenanthroline or a substituted derivative thereof, Y comprises a labile ligand and Y and R are bound to the Co(III) by coordination bonds, under conditions such that the complex covalently binds to the B-DNA or Z-DNA stereoselectively to form an adduct and irradiating the adduct so formed with ultraviolet radiation of a wavelength which is absorbed by the ligand bands of the coordination complex so as to selectively nick the B-DNA or Z-DNA.

2. A method for labeling DNA with a complex of the formula R₂ --M which comprises contacting the DNA with a complex having the formula (R₂)--M--(Y)₂, wherein R comprises 1,10-phenanthroline or a substituted derivative thereof, M comprises ruthenium (II) or cobalt (III), and Y is a labile ligand and wherein R and Y are bound to M by coordination bonds;

the contacting being effected under conditions such that the complex covalently binds to the DNA and thereby labels the DNA with a complex of the formula R₂ --M.

3. A labeled DNA molecule produced by the method of claim 2.

4. A method of claim 2, wherein the substituted derivative of 1,10-phenanthroline comprises 4,7-diamino-1,10-phenanthroline;

3,8-diamino-1,10-phenanthroline;

4,7-diethylenediamine-1,10-phenanthroline;

3,8-diethylenediamine-1,10-phenanthroline;

4,7-dihydroxyl-1,10-phenanthroline;

3,8-dihydroxyl-1,10-phenanthroline;

4,7-dinitro-1,10-phenanthroline;

3,8-dinitro-1,10-phenanthroline;

4,7-diphenyl-1,10-phenanthroline;

3,8-diphenyl-1,10-phenanthroline;

4,7-dispermine-1,10-phenanthroline, or 3,8-dispermine-1,10-phenanthroline.

5. A method of claim 2, wherein M is ruthenium (II).

6. A method of claim 2, wherein M is cobalt (III).

7. A labeled DNA molecule comprising a DNA molecule and a complex of the formula (R)₂ --M, wherein R comprises 1,10-phenanthroline or a substituted derivative thereof, wherein M comprises ruthenium (II) or cobalt (III) and wherein R is bound to M by a coordination bond, the complex being covalently bound to the DNA.

8. A labeled DNA molecule of claim 7, wherein the substituted derivative of 1,10-phenanthroline comprises 4,7-diamino-1,10-phenanthroline;

3,8-diamino-1,10-phenanthroline;

4,7-diethylenediamine-1,10-phenanthroline;

3,8-diethylenediamine-1,10-phenanthroline;

4,7-dihydroxyl-1,10-phenanthroline;

3,8-dihydroxyl-1,10-phenanthroline;

4,7-dinitro-1,10-phenanthroline;

3,8-dinitro-1,10-phenanthroline;

4,7-diphenyl-1,10-phenanthroline;

3,8-diphenyl-1,10-phenanthroline;

4,7-dispermine-1,10-phenanthroline, or 3,8-dispermine-1,10-phenanthroline.

9. A labeled DNA molecule of claim 7, wherein M is ruthenium(II).

10. A labeled DNA molecule of claim 7, wherein M is cobalt(III).