Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid

• Published in: Biometals 2010-02, Vol.23 (1), p.99-118
• Main Authors: Seng, Hoi-Ling, Von, Sze-Tin, Tan, Kong-Wai, Maah, Mohd Jamil, Ng, Seik-Weng, Rahman, Raja Noor Zaliha Raja Abd, Caracelli, Ignez, Ng, Chew-Hee
• Format: Article
• Language: English
• Subjects: Acids; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Ascorbic Acid - pharmacology; Binding Sites; Biochemistry; Biomedical and Life Sciences; Carbonyl compounds; Cell Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Computer Simulation; Crystallography, X-Ray; Cytokines; Deoxyribonucleic acid; DNA; DNA Cleavage; DNA Topoisomerases, Type I - metabolism; DNA, Superhelical - chemistry; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hydrogen peroxide; Hydrogen Peroxide - pharmacology; Life Sciences; Medicine/Public Health; Microbiology; Models, Chemical; Models, Molecular; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pharmacology/Toxicology; Phenanthrolines - chemistry; Picolinic Acids - chemistry; Plant Physiology; Plasmids - chemistry; Topoisomerase I Inhibitors; Zinc; Zinc - chemistry
• ISSN: 0966-0844; 1572-8773
• DOI: 10.1007/s10534-009-9271-y

Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-κ² N,O)₂(1,10-phenanthroline-κ² N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)₂(phen)]·5H₂O. The trans-configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G-quadruplex with human tolemeric sequence 5′-AG₃(T₂AG₃)₃-3′, can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line.