Synthesis and Antiproliferative Activity of Cisplatin-3-Chloropiperidine Conjugates

Abstract

We report the synthesis and characterization of two novel cisplatin- alkylating agents conjugates. Combining a platinum based cytostatic agent with a sterically demanding alkylating agent could potentially induce further DNA damage, block cell repair mechanisms and keep the substrate active against resistant tumor cell lines. The 3-chloropiperidines utilized as ligands in this work are cyclic representatives of the N-mustard family and were not able to coordinate platinum on their own. The introduction of a second coordination site, in form of a pyridine moiety, led to the isolation of the desired conjugates. They were characterized with HRMS, CHN-analyses and XRD. We concluded this work by examining the cytotoxicity of the ligands and the obtained complexes with MTT assays in human cancer cell lines. While the ligands showed hardly any activity, the novel conjugates both displayed a high antiproliferative and cytotoxic potency in a panel of three cell lines. Moreover, both complexes were able to largely circumvent the acquired cisplatin resistance of A2780cisR ovarian cancer cells, both in the MTT assay and a flow-cytometric apoptosis assay.

Keywords: 3-Chloropiperidines; Antitumor Agents; Cytoxicity; Medicinal Chemistry; Platinum.