Syntheses and in vitro evaluation of water-soluble "cationic metalloporphyrin-ellipticine" molecules having a high affinity for DNA.

Abstract

The synthesis of hybrid "cationic metalloporphyrin-intercalator" molecules is reported. These molecules are based on 9-methoxyellipticine as intercalator and tris-(4-N-methylpyridiniumyl)metalloporphyrins having a 4-aminophenyl or a 4-hydroxyphenyl group for the attachment of the linker. The effect of the length of linker (7-13 bonds), the chemical nature of the linking group (with a carboxamido or an ether function), the position of amino group between the two parts of hybrid molecules, the number of intercalator moieties (ellipticinium) covalently attached to the metalloporphyrin, and the nature of the central metal atom (Mn, Fe, Zn) on the biological activity of these hybrid molecules were studied. In addition, these molecules have a high affinity for double-stranded DNA (affinity constant of hybrid molecule 9Mn,Me = 2.3 x 10(9) M-1 for poly[d(A-T)] and 2.8 x 10(8) M-1 for poly[d(G-C)] and are cytotoxic against murine leukemia cells L1210 in vitro (IC50 of 9Mn,Me = 0.8 microM). Their cytotoxicities are dependent on the nature of central atom. Iron derivatives are less active than manganese analogues and the corresponding zinc derivatives are nearly inactive despite their same affinity for nucleic acids. These highly water-soluble hybrid molecules could be considered as efficient bleomycin models based on a cationic metalloporphyrin.

• Authors: L Ding, G Etemad-Moghadam, S Cros, C Auclair, B Meunier
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 34 Issue 3 Pg. 900-6 (Mar 1991) ISSN: 0022-2623 [Print] United States
• PMID: 2002470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Ellipticines
• Intercalating Agents
• Metalloporphyrins
• Pyridinium Compounds
• Water
• DNA
• Ethidium
• 9-methoxyellipticine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, therapeutic use)
• Binding, Competitive
• Chemical Phenomena
• Chemistry
• DNA (metabolism)
• Ellipticines (chemical synthesis, chemistry, therapeutic use)
• Ethidium (metabolism)
• Intercalating Agents (chemical synthesis, metabolism, pharmacology)
• Leukemia L1210 (drug therapy)
• Metalloporphyrins (chemical synthesis, chemistry, therapeutic use)
• Mice
• Pyridinium Compounds (chemical synthesis, chemistry, therapeutic use)
• Solubility
• Water