Research Projects

Programmed cell death maintains cellular homeostasis and involves apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis. Cuproptosis is a distinctive Cu-induced cell death linked to cancers like melanoma, lung, and breast cancer. It can be selectively prompted in cancer cells by Cu overload. Though the mechanism is still under exploration, Cu ionophores have been vital in its discovery by facilitating Cu transport into cells, inducing cytotoxicity in cancer cells. 1.2 Cu accumulation is vital for inducing cuproptosis in cancer cells. Ionophores have shown potential in preclinical breast cancer cell line, particularly in aggressive types like triple-negative breast cancer, that exhibit high copper levels and induce cuproptosis. Limitations of conventional therapies: ionophores offer a promising anticancer strategy. 3,4,5,6 Cu-redox cycling is essential for life, which generates ROS under unregulated conditions, leading to cell death. 7 Recently, a novel form of Cu-dependent cell death, termed cuproptosis, has been identified.8 Excess Cu, as seen in Wilson’s disease, Menkes, Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (ALS) diseases. 9,10 To address cancer more selectively, stimuli-responsive synthetic transporters have been developed to solve the selectivity issue and reduce healthy cell toxicity. Proionophores can be activated by internal or external triggers such as pH, light, voltage, enzymes, or redox signals, offering a targeted and affordable therapeutic strategy. 11 Light is one of the adaptable stimuli like tunability, distant addressability, spatiotemporal controllability, and biocompatibility. ⁸ Designing a light-responsive ion transporter possessing an inactive ‘OFF’ state and an active ‘ON’ state is challenging. We hypothesize, ion transport-related diseases can be tackled by the photo responsive selective transportation of ions across the membrane. Development of photoresponsive synthetic ionophores could be useful in fighting against cancer. To mitigate this challenge, we aim to develop a series of novel hydrophobic molecules that will reside within the membrane and selectively transport ions upon irradiation with Vis/NIR light will induce anticancer activities.12-15 We will synthesize Vis/NIR light-responsive azo-based scaffold, bis(azo)scaffold and azo-based macrocycle ionophores and light-activated pro-ionophores. Here we are proposing to induce cuproptosis, a Cu-mediated cell death, using novel photoresponsive ionophores. We believe, owing to the spatiotemporal control of light, upon irradiation with a specific wavelength, excess Cu can be delivered to the desired site to trigger cuproptosis. Additionally, the same ligand scaffold can also be used to induce ferroptosis by overloading iron.