Periodic Reporting for period 1 - MET-EFFECT (Metal complexes of a naturally inspired framework functionalized for cytotoxic andcatalytic efficiency)
Okres sprawozdawczy: 2023-01-01 do 2024-12-31
MET-EFFECT explores bioinspired metal complexes by integrating a natural flavonoid scaffold, apigenin (apg), with high-valent metal centers (Re(V) and Ir(III)), developing multifunctional compounds for medicine and catalysis. This work advances anticancer drug development and sustainable catalysis by highlighting renewable resources and fine-tuning molecular properties.
In the center of our approach is apg, a functional, naturally occurring flavonoid, known for its strong anticancer activity. We derivatized it and coordinated with high-valent metal centers, creating a molecule with tunable physicochemical properties. The synthesis of novel compounds involved an optimized strategy, yielding fully characterized ligand precursors and new Re(V) complexes. Our methodology has set up a base for the future development of Ir(III)-based systems, which are expected to provide complementary functionalities. The solubility of these complexes in water enhances their biological applicability and enables catalytic reactions in sustainable, aqueous conditions. The cytotoxicity of Re(V) and Ir(III) complexes was tested across a range of cancer cell lines. Re(V)-apg complexes demonstrated increased cytotoxicity compared to the free ligand, with a promising lead compound showing activity against T-cell leukemia. These results provide insights into structure-activity relationships (SAR) and guide modifications for improved efficacy. Beyond biomedical applications, the Re-based catalysts demonstrated catalytic activity in olefin epoxidation, offering a sustainable alternative to organic solvents. Upcoming research will explore water oxidation catalysis, crucial for artificial photosynthesis and sustainable energy conversion, with a focus on Ir(III) complexes to enable efficient oxidation. MET-EFFECT mission moves toward a sustainable future by reducing environmental impact and generating recycling protocols for common organic solvents. The next phase will address metal recycling, as recovering and reusing precious metals is a key challenge.
The R&I results emerged from 33 secondments (79 project months) and involved 20 researchers across 5 countries. These collaborations advanced career prospects, fostered teamwork, and expanded research perspectives. The team actively participated in conferences, workshops, and other outreach activities. Dissemination continues through the MET-EFFECT website, LinkedIn, and Instagram.
In the center of our approach is apg, a functional, naturally occurring flavonoid, known for its strong anticancer activity. We derivatized it and coordinated with high-valent metal centers, creating a molecule with tunable physicochemical properties. The synthesis of novel compounds involved an optimized strategy, yielding fully characterized ligand precursors and new Re(V) complexes. Our methodology has set up a base for the future development of Ir(III)-based systems, which are expected to provide complementary functionalities. The solubility of these complexes in water enhances their biological applicability and enables catalytic reactions in sustainable, aqueous conditions. The cytotoxicity of Re(V) and Ir(III) complexes was tested across a range of cancer cell lines. Re(V)-apg complexes demonstrated increased cytotoxicity compared to the free ligand, with a promising lead compound showing activity against T-cell leukemia. These results provide insights into structure-activity relationships (SAR) and guide modifications for improved efficacy. Beyond biomedical applications, the Re-based catalysts demonstrated catalytic activity in olefin epoxidation, offering a sustainable alternative to organic solvents. Upcoming research will explore water oxidation catalysis, crucial for artificial photosynthesis and sustainable energy conversion, with a focus on Ir(III) complexes to enable efficient oxidation. MET-EFFECT mission moves toward a sustainable future by reducing environmental impact and generating recycling protocols for common organic solvents. The next phase will address metal recycling, as recovering and reusing precious metals is a key challenge.
The R&I results emerged from 33 secondments (79 project months) and involved 20 researchers across 5 countries. These collaborations advanced career prospects, fostered teamwork, and expanded research perspectives. The team actively participated in conferences, workshops, and other outreach activities. Dissemination continues through the MET-EFFECT website, LinkedIn, and Instagram.
Our research involves the entire development pipeline, from molecular design and synthesis to evaluating multifunctional compounds for anticancer agents and catalysts, alongside drug delivery systems and pilot-scale production.
In the first step, the team synthesized and characterized novel ligands enhancing water tolerance in final compounds, metal complexes. This led to an optimized synthesis for a water-soluble apg ligand, establishing the way for green catalysis. Building on this, we synthesized Re(V) oxo complexes, obtaining monosubstituted complexes and expanding the Re(V) panel. Efforts continue to optimize ligands for disubstituted species. The synthesis of Ir(III) complexes remains challenging, with a modified ligand system being developed.
Cytotoxicity assays of Re(V) compounds showed moderate to significant cytotoxicity in various cancer cell lines, particularly against Jurkat leukemia cells. A SAR study using bioinformatics predicted strong potential in over 50 biological reactions. Molecular docking revealed promising interactions for cancer treatment.
The Re(V) complexes also demonstrated catalytic activity in olefin epoxidation under green conditions. Despite challenges, the results represent the first study of flavonoid-type O,O-bidentate ligand complexes in epoxidation catalysis, showing that electron-withdrawing substituents enhance activity.
The final phase focuses on integrating metallodrug candidates into microcapsules for personalized drug delivery systems (DDDS). The goal is to optimize synthesis, stability, and scale-up of microencapsulated drugs. The Rural Living Lab will validate these drugs, supporting commercialization and real-world application in cancer therapies.
In the first step, the team synthesized and characterized novel ligands enhancing water tolerance in final compounds, metal complexes. This led to an optimized synthesis for a water-soluble apg ligand, establishing the way for green catalysis. Building on this, we synthesized Re(V) oxo complexes, obtaining monosubstituted complexes and expanding the Re(V) panel. Efforts continue to optimize ligands for disubstituted species. The synthesis of Ir(III) complexes remains challenging, with a modified ligand system being developed.
Cytotoxicity assays of Re(V) compounds showed moderate to significant cytotoxicity in various cancer cell lines, particularly against Jurkat leukemia cells. A SAR study using bioinformatics predicted strong potential in over 50 biological reactions. Molecular docking revealed promising interactions for cancer treatment.
The Re(V) complexes also demonstrated catalytic activity in olefin epoxidation under green conditions. Despite challenges, the results represent the first study of flavonoid-type O,O-bidentate ligand complexes in epoxidation catalysis, showing that electron-withdrawing substituents enhance activity.
The final phase focuses on integrating metallodrug candidates into microcapsules for personalized drug delivery systems (DDDS). The goal is to optimize synthesis, stability, and scale-up of microencapsulated drugs. The Rural Living Lab will validate these drugs, supporting commercialization and real-world application in cancer therapies.
The MET-EFFECT project introduces a multifunctional molecular platform integrating biological and catalytic functionalities within a single compound. Our beyond-SOTA contributions include:
1. Advanced Ligand Modification for Water-Soluble Metal Complexes ‒ unlike traditional flavonoid derivatives, our apg ligands are functionalized to improve water solubility, enabling physiologically relevant testing and catalytic applications in aqueous media.
2. Next-Generation Metal-Flavonoid Complexes with Enhanced Biological Activity ‒ merging apg with Re(V) and Ir(III), we created stable, pure complexes with tunable cytotoxicity profiles. Our SAR analysis and molecular docking show that Re(V)-apg complexes modulate over 50 biological pathways, with selective activity against leukemia cells and structural stability in physiological conditions.
3. Metal-Based Catalysts for Green Epoxidation ‒ we introduce oxidoRe(V) catalysts with O,O-bidentate flavonoid ligands for olefin epoxidation, a first in this field. Our experiments show a correlation between electron-withdrawing substituents and catalytic efficiency.
4. Innovative Drug Delivery Solutions ‒ anticancer agents will be integrated into advanced microencapsulation systems for enhanced stability, controlled release, and bioavailability. Additionally, we will optimize microencapsulation for pilot-scale production, accelerating the transition to market-ready personalized cancer therapies.
By combining synthetic chemistry, biological testing, and formulation strategies, MET-EFFECT establishes a new frontier in metal-based drug discovery and green catalysis, bridging fundamental science with real-world applications.
1. Advanced Ligand Modification for Water-Soluble Metal Complexes ‒ unlike traditional flavonoid derivatives, our apg ligands are functionalized to improve water solubility, enabling physiologically relevant testing and catalytic applications in aqueous media.
2. Next-Generation Metal-Flavonoid Complexes with Enhanced Biological Activity ‒ merging apg with Re(V) and Ir(III), we created stable, pure complexes with tunable cytotoxicity profiles. Our SAR analysis and molecular docking show that Re(V)-apg complexes modulate over 50 biological pathways, with selective activity against leukemia cells and structural stability in physiological conditions.
3. Metal-Based Catalysts for Green Epoxidation ‒ we introduce oxidoRe(V) catalysts with O,O-bidentate flavonoid ligands for olefin epoxidation, a first in this field. Our experiments show a correlation between electron-withdrawing substituents and catalytic efficiency.
4. Innovative Drug Delivery Solutions ‒ anticancer agents will be integrated into advanced microencapsulation systems for enhanced stability, controlled release, and bioavailability. Additionally, we will optimize microencapsulation for pilot-scale production, accelerating the transition to market-ready personalized cancer therapies.
By combining synthetic chemistry, biological testing, and formulation strategies, MET-EFFECT establishes a new frontier in metal-based drug discovery and green catalysis, bridging fundamental science with real-world applications.