Ring-fused 3 beta-acetoxyandrost-5-enes as novel neuroprotective agents with cholinesterase inhibitory properties

0570474 - ÚEB 2024 RIV GB eng J - Journal Article
Gonzalez, G. - Kvasnica, Miroslav - Svrčková, K. - Štěpánková, Š. - Santos, J. R. C. - Peřina, M. - Jorda, R. - Lopes, S. M.M. - Melo, T.
Ring-fused 3 beta-acetoxyandrost-5-enes as novel neuroprotective agents with cholinesterase inhibitory properties.
Journal of Steroid Biochemistry and Molecular Biology. Roč. 225, JAN (2023), č. článku 106194. ISSN 0960-0760
R&D Projects: GA ČR GA20-15621S
Institutional support: RVO:61389030
Keywords : Neuroprotective agents * Cholinesterase inhibitors * Acetylcholinesterase and butyrylcholinesterase * enzymes * Hexacyclic steroids * SteroidalN-sulfonyl-1-azadiene
OECD category: Biochemistry and molecular biology
Impact factor: 4.1, year: 2022
Method of publishing: Open access
https://doi.org/10.1016/j.jsbmb.2022.106194

Alzheimer ' s disease (AD) is an intellectual disorder caused by organic brain damage and cerebral atrophy, characterized by the loss of memory, judgment, and abstract thinking followed by declining cognitive functions, language, and the ability to perform daily living activities. Many efforts have been made to decrease the effects of the disease but also to block the neurodegenerative process. Cholinesterase inhibitors (ChEIs) are a group of medicines that act at the neurotransmission of acetylcholine, preventing its excessive breakdown and helping to improve cognitive functions in patients with AD. In this work, 16 chiral steroids, namely ring-fused 3 beta-acetox-yandrost-5-ene derivatives, their precursor and two 16-dehydroprogesterone-derived dioximes, were assessed as cholinesterase inhibitors and neuroprotective agents. The results demonstrated that some of the tested steroids are cholinesterase inhibitors and the majority selective for acetylcholinesterase inhibition. Albeit, one ring-fused 3 beta-acetoxyandrost-5-ene containing N-methylpiperidine ring (compound 2g) demonstrated to be a selective and potent inhibitor of the butyrylcholinesterase enzyme. (S)- 4,4a,5,6,7,8-(hexahydronaphthalen-2-one)-fused 3 beta- acetoxyandrost-5-ene (compound 6) showed high neuroprotective effect, high ability to restore the mitochon-drial membrane potential from glutamate intoxication, and dramatic improvement in cell morphology. The described results provided relevant structure-activity relationship data.
Permanent Link: https://hdl.handle.net/11104/0341775