| Popis: |
Cancer remains a global epidemic, with millions affected by the Non-Communicable Disease (NCD) annually. While cisplatin and its platinum(II) derivatives remain widely used chemotherapeutic agents, the undesirable side effects associated with the use of these metallodrugs and the evolution of resistance by cancers limit the scope of use of these platinum(II) complexes. Working towards addressing these issues, research has focused on the development of chemotherapeutic agents based on alternate platinum-group metals (PGMs), with ruthenium metallodrugs being among the most successful in this category. The combination of pharmacophores onto dendritic scaffolds and the combination of these scaffolds with PGMs, yielding multinuclear organometallic complexes is a strategy that has been widely used in rational drug design. However, there is limited research into multinuclear ruthenium compounds, specifically trimetallic ruthenium compounds. With this in mind, the purpose of this study was to synthesize and characterize a series of 2,5-disubstituted benzimidazole-based trimeric compounds and related trinuclear complexes bearing ruthenium(II) metal centers at the periphery. All of the synthesized compounds were screened for their in vitro cytotoxicity against the MCF-7 and MDA-MB-231 breast cancer cell lines and the 501 melanoma cell line. A series of 2,5-disubstituted benzimidazole trimeric ligands were prepared from the cyclocondensation reaction of trimeric o-phenylenediamines with either benzaldehyde or 2-pyridinecarboxaldehyde. Complexation of these 2,5-disubstituted tris-benzimidazole ligands with [RuCl(µ-Cl)(p-cymene)]2 afforded the respective trinuclear neutral CN-chelated and cationic NN-chelated ruthenium(II) complexes. In addition to this, a series of 2-ferrocenyl benzimidazole trimeric compounds were synthesized as non-planar bioisosteres of the 2-aryl 5-substituted benzimidazole trimeric ligands. All of the synthesized compounds were fully characterized using an array of spectroscopic (1H, 13C{1H}, 31P{1H} and 19F{1H} NMR, FT-IR spectroscopy) and analytical (mass spectrometry and elemental analysis) techniques. Preliminary cytotoxic screening of all of the synthesized compounds against the MCF-7 breast adenocarcinoma cell line was done. This preliminary investigation revealed that the 2-pyridyl trimeric ligands and the corresponding trinuclear cationic complexes show superior activity relative to their respective 2-phenyl trimeric ligand counterparts and the corresponding neutral cyclometallated complexes. Consequently, the 2-pyridyl tris-benzimidazole ligands and their corresponding cationic complexes were selected for cytotoxic evaluation against additional cancer cell lines (the MDA-MB-231 breast cancer and the 501mel cancer cell lines). Overall, a 2-pyridyl tris-benzimidazole ligand and two trimetallic cationic complexes showed anticancer activity either comparable or superior to that of cisplatin against the MCF-7 breast cancer cell line (IC50 ≤ 35 µM). Additionally, a 2-pyridyl trimeric benzimidazole ligand and a trimetallic cationic NN-ruthenium(II) complex showed mild activity against the MDA-MB-231 and 501mel cancer cell lines, respectively (IC50 < 35 µM in both cell lines). Selectivity studies based on the non-tumorigenic MCF-12A breast epithelial cell line indicated that selected compounds had low cytotoxicity towards non-tumorigenic cells and showed enhanced selectivity towards the MCF-7 cancerous cells relative to cisplatin. Solvent stability studies of the cationic NN-ruthenium(II) complexes show that these compounds are stable in DMSO for 48 hours under physiological conditions. Additionally, preliminary mechanistic studies of the most active complex indicate that the complex does not interact with guanosine 5’-monophosphate (5’-GMP), suggesting that this complex elicits cytotoxicity via an alternative mechanism of action. |
