Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate

Abstract

The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1–CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NFκB, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.

Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases

“…Moreover, DMF and MMF treatment in animal and primary cultures of CNS cells have been reported to increase the nuclear levels of Nrf2, resulting in increases in the cellular redox potential, GSH and ATP levels, and ΔΨm [ 175 ]. In neurons and astrocytes, DMF and MMF were found to be cytoprotective against OS-induced cellular injury and death, in addition to significantly improving cell viability via upregulation of the Nrf2-dependent antioxidant response, indicated by the intracellular regulation of GSH [ 176 , 177 , 178 ]. Other studies have demonstrated improvements in mitochondrial function following DMF and MMF treatment by upregulating mitochondrial biogenesis in an Nrf2-dependent manner [ 175 ].…”

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis

“…The transcription factor Nrf2 has been identified as the main therapeutic target of DMF in several cell types 42 , 46 – 48 . Electrophilic agents such as DMF and its active metabolites (e.g monomethyl fumarate (MMF)) facilitates Nrf2 activation via Keap1 49 , 50 .…”

Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

“…[63] However, the only case study reported so far is a recent series of vinyl sulfoximines which activate the transcription factor Nrf2. [64] While Nrf2 is considered the main target of the multiple sclerosis drug dimethyl fumarate (43, Figure 18), exploration of additional Nrf2-activating compounds is motivated by its significant off-target effects and low CNS penetration. Against this backdrop, vinyl sulfones like VSC2 (44, Figure 18) were recently shown to increase Nrf2 levels via covalent interaction with certain cysteines in Keap1, leading to Nrf2 activation.…”

“…[65] Carlström and co-workers have evaluated a series of VSC2 sulfoximine analogues employing a broad variety of substituents at the sulfoximine nitrogen. [64] The N-methyl analogue CH-3 (45, Figure 18) and dimethyl fumarate displayed comparable activation of Nrf2 in vitro, but N-methyl sulfoximine 45 revealed less off-target effects in vitro and in vivo. Unfortunately, the publication does not provide any insights into the mode of action of vinyl sulfoximine CH-3, but studies with structurally related chalcones and vinyl sulfones suggest that the compound is acting as a covalent inhibitor.…”