Novel triterpene derivatives were prepared and evaluated in salsolinol (SAL)- and glutamate (Glu)-induced models of neurodegeneration in neuron-like SH-SY5Y cells. Among the tested compounds, betulin triazole 4 bearing a tetraacetyl-β-d-glucose substituent showed a highly potent neuroprotective effect. Further studies revealed that removal of tetraacetyl-β-d-glucose part (free triazole derivative 10) resulted in strong neuroprotection in the SAL model at 1 μM, but this derivative suffered from cytotoxicity at higher concentrations. Both compounds modulated oxidative stress and caspase-3,7 activity, but 10 showed a superior effect comparable to the Ac-DEVD-CHO inhibitor. Interestingly, while both 4 and 10 outperformed the positive controls in blocking mitochondrial permeability transition pore opening, only 4 demonstrated potent restoration of the mitochondrial membrane potential (MMP) in the model. Derivatives 4 and 10 also showed neuroprotection in the Glu model, with 10 exhibiting the strongest oxidative stress reducing effect among the tested compounds, while the neuroprotective activity of 4 was probably due recovery of the MMP.

Department of Medicinal Chemistry Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University in Olomouc Hnevotinska 5 779 00 Olomouc Czech Republic

Department of Neurology University Hospital Olomouc and Faculty of Medicine and Dentistry Palacký University Olomouc CZ 775 20 Olomouc Czech Republic

Department of Organic Chemistry Faculty of Science Palacky University 17 Listopadu 1192 12 771 46 Olomouc Czech Republic

Laboratory of Growth Regulators Faculty of Science Palacký University and the Institute of Experimental Botany of the Czech Academy of Sciences Šlechtitelů 27 CZ 78371 Olomouc Czech Republic

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