Toward Efficient Zn(II)-Based Artificial Nucleases

• Published in: Journal of the American Chemical Society Vol. 126; no. 14; pp. 4543 - 4549
• Main Authors: Boseggia, Elisa, Gatos, Maddalena, Lucatello, Lorena, Mancin, Fabrizio, Moro, Stefano, Palumbo, Manlio, Sissi, Claudia, Tecilla, Paolo, Tonellato, Umberto, Zagotto, Giuseppe
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.04.2004; Amer Chemical Soc
• Subjects: Anthraquinones - chemical synthesis; Anthraquinones - chemistry; Anthraquinones - pharmacology; Biological and medical sciences; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Chemistry; Chemistry, Multidisciplinary; Cyclohexanes - chemical synthesis; Cyclohexanes - chemistry; Cyclohexanes - pharmacology; Deoxyribonucleases - chemistry; Deoxyribonucleases - pharmacology; Fundamental and applied biological sciences. Psychology; Intercalating Agents - chemical synthesis; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Mechanisms. Catalysis. Electron transfer. Models; Models, Molecular; Molecular biophysics; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Physical chemistry in biology; Physical Sciences; Plasmids - chemistry; Plasmids - metabolism; Science & Technology; Zinc - chemistry; Zinc - pharmacology; CONFORMATIONAL ENERGIES; ACID; DNA HYDROLYSIS; COMPLEXES; MMFF94; HYDROLYTIC CLEAVAGE; ION CATALYSIS; BINDING; DERIVATIVES; MOLECULAR-FORCE FIELD; Kinetic control; DNA; Molecular dynamics method; Theoretical study; Hartree Fock method; Transition metal Complexes; Experimental study; Chemical reactivity; Zinc Complexes
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja039465q

A series of cis-cis-triaminocyclohexane Zn(II) complex−anthraquinone intercalator conjugates, designed in such a way to allow their easy synthesis and modification, have been investigated as hydrolytic cleaving agents for plasmid DNA. The ligand structure comprises a triaminocyclohexane platform linked by means of alkyl spacers of different length (from C4 to C8) to the anthraquinone group which may intercalate the DNA. At a concentration of 5 μM, the complex of the derivative with a C8 alkyl spacer induces the hydrolytic stand scission of supercoiled DNA with a rate of 4.6 × 10-6 s-1 at pH 7 and 37 °C. The conjugation of the metal complex with the anthraquinone group leads to a 15-fold increase of the cleavage efficiency when compared with the anthraquinone lacking Zn-triaminocyclohexane complex. The straightforward synthetic procedure employed, allowing a systematic change of the spacer length, made possible to gain more insight on the role of the intercalating group in determining the reactivity of the systems. Comparison of the reactivity of the different complexes shows a remarkable increase of the DNA cleaving efficiency with the length of the spacer. In the case of too-short spacers, the advantages due to the increased DNA affinity are canceled due to the incorrect positioning of the reactive group, thus leading to cleavage inhibition.