Topoisomerase I inhibition and DNA cleavage by zinc, copper, and nickel derivatives of 2-[2-bromoethyliminomethyl]-4-[ethoxymethyl]phenol complexes exhibiting anti-proliferation and anti-metastasis activity

• Published in: Journal of inorganic biochemistry Vol. 159; pp. 14 - 21
• Main Authors: Lee, Sze Koon, Tan, Kong Wai, Ng, Seik Weng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2016
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Copper; Copper - chemistry; Copper - pharmacology; DNA; DNA, Bacterial - metabolism; Escherichia coli - genetics; Escherichia coli - metabolism; Humans; Neoplasm Metastasis; Neoplasms - drug therapy; Neoplasms - metabolism; Nickel; Nickel - chemistry; Nickel - pharmacology; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Schiff base; Topoisomerase; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - chemistry; Topoisomerase I Inhibitors - pharmacology; Zinc; Zinc - chemistry; Zinc - pharmacology; Schiff base; Topoisomerase; Nickel; Copper; DNA; Zinc
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.02.010

Three transition metal derivatives (Zn, Cu, and Ni) of 2-[2-bromoethyliminomethyl]-4-[ethoxymethyl]phenol (L) were synthesized by the reaction of the metal salts with the Schiff base ligand in one pot. In the crystal structure of [Zn(L)Br], the Schiff base ligand binds to the metal center through its phenolate oxygen and imine nitrogen, and adopts a distorted tetrahedral geometry. These compounds were found to inhibit topoisomerase I (topo I) activity, induce DNA cleavage and show DNA binding activity. Moreover, these compounds were found to be cytotoxic towards several cancer cell lines (A2780, MCF-7, HT29, HepG2, A549, PC3, LNCaP) and prevent metastasis of PC3. Collectively, Cu(II) complex 2 shows superior activity relative to its Zn(II) and Ni(II) analogs. These complexes were able to aim multiple targets (inhibit topoisomerase I activity and cleave/bind DNA) and showed dual actions: anti-proliferation and anti-metastasis. [Display omitted] •Schiff base ligand containing ethoxy and bromoethyl group was prepared.•Zn, Cu, and Ni complexes of above Schiff base were synthesized and characterized.•These complexes were able to inhibit topoisomerase I activity and cleave/bind DNA.•These complexes also showed dual actions: anti-proliferation and anti-metastasis.•Cu complex exhibited relatively greater activity than Zn and Ni analogs.