Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

Abstract

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (<b>6a</b>-<b>6c</b>) were synthesized as antitumor agents. Compounds <b>6a</b> and <b>6c</b> exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, <b>6a</b> effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of <b>6a</b> and <b>6c</b>, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that <b>6a</b> and <b>6c</b> arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, <b>6a</b> and <b>6c</b> caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca²⁺ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that <b>6a</b> and <b>6c</b> exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.