| dc.description.abstract | Efficient cellular delivery of bioactive molecules is essential for the discovery and development of novel drugs. However, targeting intracellular proteins in the cytosol and other cellular components using small molecules remains a significant challenge. Therefore, it is necessary to develop new delivery strategies for the enhanced cellular uptake and more organelle-targeted delivery of the therapeutics. For this purpose, various strategies have been developed, including prodrugs, thiol-mediated approaches, and more recently, the use of non-covalent interactions. My thesis work focuses on improving the cellular uptake of small molecules by incorporating chalcogen atoms. We designed molecules by incorporating chalcogen atoms (ranging from oxygen to tellurium) into the diphenyl moiety and attaching them to suitable fluorophores. Our studies revealed a remarkable increase in the uptake of selenium- and tellurium-containing compounds compared to their lighter chalcogen counterparts. Furthermore, we demonstrated that cellular uptake could be modulated by fine-tuning the chalcogen-bond (ChB) donor properties through the introduction of electron-withdrawing and electron-donating groups. Using this strategy, compounds with dansyl, coumarin, and negatively charged fluorophores were successfully transported into mammalian cells.
We also explored the interplay between chalcogen and halogen bonds in cellular uptake when both chalcogen and halogen atoms are present within the same molecular entity. For this study, we selected a tricyclic moiety with a chalcogen atom at the core of the structure. By changing the chalcogen atom from oxygen to selenium and introducing halogens (F to I) at the same molecular entity, we investigated the potential competition between these two types of interactions. Our detailed study revealed that, in the case of phenoxazine having oxygen atom, cellular uptake occurred predominantly via halogen bond-mediated recognition. In contrast, for phenothiazine and phenoselenazine compounds, which contain sulfur and selenium atoms, respectively, the uptake was mediated through the chalcogen-bond-mediated recognition process. We further extended our concept by designing a fluorescent probe for alkaline phosphatase (ALP) detection, incorporating a chalcogen-containing recognition moiety. The ratiometric fluorescent probe that included both chalcogen and halogen moieties, featuring a 1,4-naphthalimide core and a phosphate group. Cell-based studies demonstrated significantly higher cellular efficiency and improved sensitivity for the selenium-containing fluorescent probes compared to the other derivatives. Finally, we investigated the effect of chalcogen substitution on the solvatochromic fluorescent probes by designing a series of D-π-A system-based molecular rotors, which exhibit fluorescence through a Twisted Intramolecular Charge Transfer (TICT) mechanism. Polarity-dependent studies showed a quenching of fluorescence when transitioning from non-polar to polar solvents, whereas in high-viscosity solvents, a significant increase in fluorescence intensity was observed. | en_US |
