Copper(II) complexes of Schiff base ligands as promising anticancer agents

Based on World Health Organization (WHO) report, it was estimated that one in five people before age 75 will suffer from cancer during their lifetime, and more than 13 million cancers death will happen in 2030. Chemotherapy is a basic approach for the treatment of cancer diseases. However, because of drug resistance and considerable side effects drug-induced toxicity, the discovery of new metal analogs with promising activity and high therapeutic index is an urgent need. The fundamental role of copper and the recognition of its complexes as important bioactive compounds in vitro and in vivo aroused an ever-increasing interest in these agents as potential drugs for therapeutic intervention in various diseases. Schiff bases are a critical class of compounds in medical chemistry that have demonstrated significant chemotherapeutic and antibacterial application. Schiff base Cu(II) complexes revealed great potential for antiproliferative, antibacterial, and gastroprotective activity. Coumarins are a wide class of natural and synthetic compounds that showed diverse pharmacological activities including anticancer activity. Among the wide variety of coumarins, 7-hydroxycoumarin derivatives have been shown to possess desirable antiproliferative activities. In particular, their antibacterial, antifungal and anticancer activities make the compounds attractive for further derivatization and screening as novel therapeutic agents. Taking these compounds as lead, we have designed and synthesized a series of new copper(II) complexes with coumarin-derived Schiff base ligands. Two series of Schiff bases were prepared by condensation of 8-formyl-7-hydroxy-4-methylcoumarin and 8-acetyl-7-hydroxy-4-methylcoumarin with p-substituted aniline derivatives. These compounds were used as ligands in the synthesis of copper(II) complexes. The obtained Schiff bases as well as copper complexes are mostly novel molecules. Only the products of condensation 8-formyl-7-hydroxy-4-methylcoumarin with p-toluidine and 8-acetyl-7-hydroxy-4-methylcoumarin with p-toluidine and its copper(II) complex were synthesized, but the anticancer activity of these compounds was not determined. The assay of their cytotoxic activity is in progress. Preliminary, we have identified two copper(II) coordination compounds of 7-hydroxy-8-[1-(4-methoxyphenyl imino)ethyl]-4-methyl-2H-chromen-2-one and 7-hydroxy-8-[1-(4-hydroxyphenyloimino)ethyl]-4-methyl-2H- chromen-2-one having dose-dependent antiproliferative activity on HeLa cancer cell line. Additionally, the Schiff bases – derivatives of substituted salicylaldehydes and 2-hydroxyacetophenones condensed with appropriate anilines were prepared. Such compounds have been reported in scientific papers, their copper complexes have not been assayed yet, and may serve as an useful tool in QSAR investigation.