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

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 3ß-acetoxyandrost-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 3ß-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 3ß-acetoxyandrost-5-ene (compound 6) showed high neuroprotective effect, high ability to restore the mitochondrial membrane potential from glutamate intoxication, and dramatic improvement in cell morphology. The described results provided relevant structure-activity relationship data.

Reactivity of steroidal 1-azadienes toward enamines: an approach to novel chiral penta- and hexacyclic steroids.

The chemical behavior of steroidal N-sulfonyl-1-azadienes toward carbonyl compounds, in the presence of pyrrolidine, is described. With aldehydes, these azadienes participate in hetero-Diels-Alder reactions with the in situ generated enamines. The stereoselectivity results from the approach of the dienophiles from the less hindered α-face of the steroid, with the pyrrolidine moiety endo and retention of the enamine trans geometry. This diastereoselective synthetic methodology led to a new class of chiral pentacyclic steroids. Interestingly, the studied steroidal scaffolds follow a different mechanistic pathway with cyclic ketones. They undergo a diastereoselective annulation reaction, under enamine catalysis, affording chiral hexacyclic steroids.