Synthesis of copper and zinc 2-(pyridin-2-yl)imidazo[1,2-a]pyridine complexes and their potential anticancer activity

• Published in: European journal of medicinal chemistry 2017-01, Vol.126, p.353-368
• Main Authors: Dam, Jean, Ismail, Zeenat, Kurebwa, Taurai, Gangat, Nadia, Harmse, Leonie, Marques, Helder M., Lemmerer, Andreas, Bode, Moira L., de Koning, Charles B.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Breast cancer (MCF-7 and MDA-MB-231); Cell Proliferation - drug effects; Copper - chemistry; Copper and zinc imidazo[1,2-a]pyridines; Drug Screening Assays, Antitumor; Drug Stability; Fluorescence microscopy; HL-60 Cells; Humans; Leukemia (K562 and HL-60) and colorectal cancer (HT-29); MCF-7 Cells; Multicomponent coupling reactions; Necrosis and paraptosis; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pyridines - chemistry; Zinc - chemistry
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.10.041

A small library of novel copper and zinc imidazo[1,2-a]pyridine complexes have been synthesized. Their structures were confirmed by X-ray diffraction crystallography and a selection of these compounds was tested against five cancer cell lines originating from breast cancer (MCF-7 and MDA-MB-231), leukemia (K562 and HL-60) and colorectal cancer (HT-29). The imidazo[1,2-a]pyridines and their zinc complexes showed poor anticancer activity, while the copper complexes were active against the cancer cell lines with IC50 values comparable to and lower than camptothecin. For example, copper 6-bromo-N-cyclohexyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine acetate 21 had an IC50 value lower than 1 μM against the HT-29 cells. Fluorescence microscopy with acridine orange, Hoechst 33342 and ethidium bromide, used in a preliminary investigation to evaluate morphological changes showed that copper 6-bromo-N-cyclohexyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amine acetate 21 caused both apoptosis, necrosis and paraptosis in the MCF-7 and HL-60 cells. A select group of copper N-cyclohexyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amines (26, 27, 29 and 31) induced apoptosis, paraptosis and deformed nuclei in MCF-7 cells. A small library of novel copper and zinc 2-(pyridin-2-yl)imidazo[1,2-a]pyridine complexes synthesized showed significant activity against cancer cell lines originating from breast cancer leukemia (K562 and HL-60) and colorectal cancer (HT-29). [Display omitted] •Copper and zinc 2-pyridin-2-yl-imidazo[1,2-a]pyridine complexes synthesized.•Good anticancer activity of copper-imidazo[1,2-a]pyridines against 5 cancer cell lines.•Fluorescence microscopy to evaluate morphological changes during cell death.