From the inception of the project to the current period covered by the report, significant progress has been made in the development of hypoxia and redox-activated G4 DNA targeting platinum prodrugs. The following summarizes the key activities and main results achieved:
1. Compound Design and Synthesis: Extensive efforts have been dedicated to designing and synthesizing novel platinum-based metal complexes capable of selectively binding to G4 DNA structures. Through rational design strategies, several lead compounds have been synthesized and characterized to study the binding affinity and specificity to duplex and quadruplex DNA structures.
2. Activation Mechanisms: Detailed studies have been conducted to elucidate the activation mechanisms of the prodrugs in presence of reducing environments typically found in tumor microenvironments. The results have provided insights into the structural and electronic properties along with modifications necessary for effective activation in tumor environments.
3. Evaluating the affinities towards different forms of DNA structures (duplex and G4 DNAs) and quadruplex topologies. The DNA binding studies with quadruplex sequences having different topologies revealed that PtIV prodrugs having no affinity towards various forms of DNA structures whiles upon cellular activation via reduction, its active counterpart PtII shown excellent binding towards G4s and no affinity towards genomic duplex DNA.
4. In vitro Evaluation: The efficacy and specificity of the synthesized compounds have been evaluated through extensive in vitro studies using cancer cell lines and relevant cellular models. Moreover, detailed studies regarding in vitro cytotoxicity in hypoxic and normoxic condition in different cancer cells, cellular uptake and investigation of mechanism of action have been planned.
5. Exploitation and Dissemination: The results obtained from this project is being prepared as a manuscript titled as “Activation of Pt(IV) complexes under hypoxic conditions yielding Pt(II) complexes with high affinity for G4 DNA” and will be communicated soon. Another paper originated, have been disseminated through a peer-reviewed journal as Reyes, J. B., Sherin, P. S., Sarkar, A., Kuimova, M. K., & Vilar, R. (2023). Platinum(II)-Based Optical Probes for Imaging Quadruplex DNA Structures via Phosphorescence Lifetime Imaging Microscopy. Angewandte Chemie International Edition, 62(42), e202310402.
In conclusion, the project work has significantly advanced our understanding of hypoxia and redox-activated triggered platinum-based G4 binding agents as potential anticancer therapeutics. The main results achieved underscore the feasibility of this innovative approach for targeted cancer treatment. Moving forward, further optimization and validation of the lead compounds will be pursued towards clinical translation, focusing on maximizing therapeutic efficacy and minimizing off-target effects.
