An efficient molecular luminophore based on tetraphenylethylene (TPE) enabling intracellular detection and therapeutic benefits of hydrogen sulfide in Alzheimer’s disease

Abstract

Hydrogen sulfide (H2S), an essential neurotransmitter, regulates physiological processes, including brain function. Lower level of endogenously produced H2S may lead to Alzheimer’s disease (AD), which is a progressive neurodegenerative disorder characterized by the deposition and aggregation of amyloid-beta (Aβ) peptides in the brain tissue. Developing a molecular probe enabling sensing and visualizing of Aβ-disaggregates caused by H2S would be a potential therapeutic benefit for Alzheimer’s disease. Herein, we report a rational design and synthesis of an orthogonally substituted tetraphenylethylene (TPE) dual functional turn-on molecular luminophore TPE-NBD-D. The current strategy centers on a TPE-core appended with an ancillary H2S sensing unit i.e., 4-chloro-7-nitrobenzofurazan (NBD) and a disulfide linked donor (D: 4-(pyridin-2-yldisulfaneyl)-benzoate) as a source of H2S in presence of bio-thiols. The disulfide-linked H2S-donor is cleaved off from the TPE by esterase and its counterpart exhibited a turn-on fluorescence response after releasing NBD ligand in bio-thiol environments. Molecular probe TPE-NBD-D, showed a marked efficiency to detect H2S in solution state (LOD 0.1 µM) through AIE phenomenon and featured its aqueous solubility, cell membrane permeability, low cytotoxicity and high selectivity towards H2S. The probe enabled to detect intracellular H2S in neuroblastoma cell line SHSY-5Y as reflected by the turn-on fluorescence. Further, the TPE-NBD-D has been employed in vivo mice model where the probe is capable of releasing H2S in thiol abundant colorectal area and opens up a new insight to understand the involvement of H2S releasing molecules in the management of Alzheimer’s disease (AD). Eventually, the H2S production by TPE-NBD-D has been demonstrated to induce the Aβ1–42 de-agglomeration which is meticulously monitored by the AFM, SEM and Raman fingerprint analysis of the model agglomerated form of Aβ1–42 protein. This is the first time, we revealed TPE-structured molecular probe enabling as H2S donor and utilized for amyloid beta de-agglomeration without imparting any cytotoxicity. Therefore, this probe may be a potential chemical tool for the diagnosis and treatment of AD.