Bifunctional molecules having a DNA intercalator or DNA groove binder linked to ethylene diamine tetraacetic acid

• US 4,665,184 A
• Filed: 05/07/1986
• Issued: 05/12/1987
• Est. Priority Date: 10/12/1983
• Status: Expired due to Fees

• Current Assignee: California Institute of Technology
• Original Assignee: California Institute of Technology
• Inventors: Hertzberg, Robert P., Dervan, Peter B.
• Primary Examiner(s): Hollrah, Glennon H.
• Assistant Examiner(s): Turnipseed, James H.
• Application Number:
  US06/860,604
• Time in Patent Office: 370 Days
• Field of Search: 546/109
• US Class Current: 546/109
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 221/12 Phenanthridines

Abstract

Novel bifunctional molecules having a DNA intercalator or DNA groove binder linked to ethylene diamine tetraacetic acid such as compounds having the formula: ##STR1## wherein R is methyl or ethyl. Also, the method of cleaving DNA by contact with one of the above-identified molecules in the presence of ferrous ion and oxygen.

The process of preparing said molecules by the reaction of P-carboxy methidium halide, p-carboxy ethidium halide, or other DNA intercalator or DNA groove binder with 1-3-diaminopropane followed by condensation with ethylenediamine tetraacetic acid.

Distamycin-EDTA.Fe(II)(DE.FE(II)) contains EDTA attached to the amino terminus of the groove binder tripeptide (tris-N-methylpyrrolecarboxamide). DE.Fe(II) cleaves DNA contiguous to a five base pair A+T rich sequence. This is a novel and unique molecule and superior in sequence specificity to the naturally occurring antitumor compound used in man, bleomycin which cleaves DNA at a two base pair recognition site. EDTA-distamycin-Fe(II)(ED.Fe(III)) contains EDTA attached to the carboxy terminus of the groove binder tripeptide, tris-N-methylpyrrolecarboxamide. ED.Fe(II) cleaves DNA contiguous to a five base pair A+T rich sequence. Penta-N-methylpyrrolecarboxamide-EDTA.Fe(II)(P5E.Fe(II)) cleaves DNA on opposite strand at the six base pair recognition level in a catalytic reaction. This is the first designed synthetic molecule that approximates the double strand sequence specific cleavage of DNA(4-6 bp recognition level) by the natural substance restriction enzymes, tools which make possible recombinant DNA manipulations. P5E.Fe(II) cuts DNA at sequences not available by the naturally occurring restriction enzymes.

The dimers, bis(EDTA-distamycin.Fe(II) and EDTA-bisdistamycin.Fe(II) which double strand cleave DNA at the eight base pair recognition level (A+T rich).

Claims

1. The compounds having the general formula:

##STR10## wherein R is methyl or ethyl.

2. The composition of claim 1 wherein the compound is methidiumpropyl ethylenediamine tetraacetic acid.

3. The composition of claim 1 wherein the compound is ethidiumpropyl ethylenediamine tetraacetic acid.