Enhancing the anticancer potency of titanium(IV) chemical transferrin mimetic complexes and exploring their antimicrobial therapeutic potential.

Abstract

A very promising direction in the development of anticancer drugs is inhibiting intracellular iron (Fe) bioavailability because Fe, although it is an essential metal, plays a major role in cancer cell proliferation. Cancer cells have a higher requirement for Fe than healthy cells to meet their greater metabolic demand. As such cancer cells overexpress the transferrin receptor, a membrane bound protein, to uptake Fe(III) from blood. They also increase Fe retention by shutting down the export membrane transport proteins. The net effect is an increased labile iron pool that is readily accessible for functionalization. The compound Ti(deferasirox)₂, previously developed in the Tinoco laboratory, can operate intracellularly to decrease the levels of functional Fe by reacting with the labile iron pool via transmetalation. In this process the ligand, deferasirox, binds Fe(III) creating a highly stable Fe(III) complex that makes Fe functionally inert. Simultaneously, the Ti(IV) is released into the cytosol, where it is able to bind to Fe free biomolecular sites including the enzyme ribonucleotide reductase (RNR), responsible for producing the building blocks for DNA replication. RNR has a diiron binding site and it depends on the redox activity of Fe to become activated. As a redox inert metal, Ti(IV) binding at the diiron site would prevent RNR activation and has the potential to effectively block Fe binding. Due to the potency of Ti(deferasirox)₂ being limited to only targeting the Fe(III) pool combinatorial treatment of Ti(deferasirox)₂ with the Fe(II)/Fe(III) chelator triapine and the well-known, chemotherapeutic drug, cisplatin, was performed. Triapine is a RNR inhibitor and is of the newest and most promising chemotherapeutic compounds with great success in phase I and II clinical trials. The human T-lymphocyte cell line Jurkat, the cancerous human lung alveolar epithelial cell line A549, and the human lung fibroblast cell line MRC-5 were utilized as in vitro models for examining the cytotoxic behavior for the combination of Ti(deferasirox)₂ with triapine and cisplatin. Results showed a variety of effects including additive and near synergistic effects among combinations tested. Moreover, this work discloses is a new transmetalation drug strategy by enhancing the chelator template by creating a dual chelator ligand for the targeting of intracellular labile Fe and the cellular delivery of cytotoxic metals. For this strategy, triapine was conjugated to deferasirox because it has the capacity to bind at the diiron site of RNR. This conjugated ligand features hard and soft Lewis base chelators to facilitate effective Fe(II)/Fe(III) binding and the development of heterometallic compounds using Ti(IV), Au(I), and Pt(II). The ligand also demonstrates superior cytotoxicity against the Jurkat cell line versus deferasirox and triapine alone and strong potency against a broad range of cancer cell lines. Given the limited knowledge on the antimicrobial activity of titanium(IV), eight Ti(IV) complexes and some of their corresponding ligands were screened by the Community for Open Antimicrobial Drug Discovery for antimicrobial activity. Two of the Ti(IV) compounds including the Ti(deferasirox)₂ exhibited significant activity against the bacteria lines tested. The ability of this compound to undergo transmetalation with labile Fe(III) sources and, as a consequence, inhibit Fe bioavailability and RNR is evaluated as a possible mechanism for its antibiotic effect.