Project Title: Bimetal compounds that synergize cytotoxic metals and dual intracellular chelation of copper and iron
Research overview: Basic research is leading the way to new FDA approved drugs and has led to groundbreaking insights in understanding the complex nature of cancer. The advent of omics-based research has led to identifying new potential drug targets. Nonetheless, the long time to advance a new drug from the benchtop to the market is a major global health problem. Current classes of anticancer drugs feature rich structural diversity but exhibit narrow spectrum of effect and limited timespan of application due to toxicity, side effects, and cellular resistance. To expand the toolset of anticancer strategies for clinical application, a metal-centric drug design will be engineered to target and alter the functionality of essential metals that fuel cancer and introduce cytotoxic metals of well-characterized cell attack mechanisms. Copper (Cu) and iron (Fe) are two essential metals that are intimately connected in several biological processes of the human body and are vital to the growth, rapid proliferation, and metastasis of cancer cells. Chelators of Cu and Fe metals ions have demonstrated promise for anticancer drug development. To date, however, no chelation approach simultaneously tackles both metal ions and exploit the metal binding properties of the chelators to deliver cytotoxic metals. The P.I.’s laboratory was the first to demonstrate the feasibility of coupling titanium(IV) (Ti(IV)) with ferric chelators to inhibit the bioavailability and functionality of intracellular Fe and enable Ti(IV) inhibition of the DNA synthesis and repair Fe-dependent ribonucleotide reductase (RNR) via a process of intracellular transmetalation with the labile iron pool (LIP). Since then the P.I.’s laboratory is working on the development of small molecule conjugate of the Fe(II)/Fe(III) chelators to extensively target the intracellular LIP. These dual chelator (DC) conjugates will used to create heterobimetal compounds that synergize cytotoxic metals having different cell targets with Fe/Cu chelation. These compounds will operate in the intracellular environment to release cytotoxic metals and scavenge cellular Fe(II)/Fe(III) and Cu(II), transforming them into redox active, cell attack agents. REU: PR-CLIMB participantss who participate in this project will take a mechanism guided approach to establish bimetal compounds that activate apoptotic and ferroptotic cell death routes and determine the cell targets and cytotoxic contributions of the dual chelation and the metal ions in different cell types.
Skills/Techniques: REU:PR-CLIMB participants will be immersed in organic and coordination compound synthesis and characterization and will learn cell culturing techniques and cell assays to study the mechanism of action of anticancer metal compounds.
Skills/Techniques: REU:PR-CLIMB participants will be immersed in organic and coordination compound synthesis and characterization and will learn cell culturing techniques and cell assays to study the mechanism of action of anticancer metal compounds.
To contact Dr. Tinoco you can write to the address below
E-mail: [email protected]
Also visit his laboratory website: https://tinocolab.weebly.com/
E-mail: [email protected]
Also visit his laboratory website: https://tinocolab.weebly.com/