Isofagomine-coumarin hybrids: bridging cancer and Alzheimer's disease

Given the urgent need for developing new therapeutic strategies against chronic diseases such as neurodegeneration and cancer, and the evidence of shared biochemical pathways linking Alzheimer's disease to certain types of cancer, we have designed a novel family of multifaceted compounds to target both diseases. For that purpose, isofagomine (a relevant azasugar) – coumarin hybrids were prepared and tested in vitro as potential dual-action molecules. Key structural variations, including different hydroxyl group substitutions and changes in the length of the hydrocarbon linker, had minimal impact on cholinesterase inhibition. All compounds exhibited strong inhibition of butyrylcholinesterase (BuChE), representing the predominant cholinesterase in moderate-to-advanced stages of Alzheimer's disease, with IC50 values in the single-digit micromolar concentration range. Additionally, the isofagomine-coumarin hybrids displayed remarkable selectivity, up to 177-fold, for human BuChE over human acetylcholinesterase (AChE). Docking simulations predicted derivatives to be accommodated within the BuChE binding region. Additionally, the compounds showed reduced neurotoxicity and moderate neuroprotection. Furthermore, a direct correlation was observed between tether length and antiproliferative activity, with the lead compound exhibiting potent effects in the low-micromolar range. 3D Holotomographic microscopy, through continuous live-cell imaging, proved mitotic arrest followed by apoptotic events to be involved in their mode of action. Azasugar-coumarin hybrids constitute promising multifaceted molecules in terms of therapeutics or prevention of neurodegeneration and cancer.