Structure–Activity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents

Abstract

Historically known for its role in blood coagulation and bone formation, Vitamin K (VK) has begun to emerge as an important nutrient for brain function. While VK involvement in the brain has not been fully explored, it is well known that oxidative stress plays a critical role in neurodegenerative diseases. It was recently reported that VK protects neurons and oligodendrocytes from oxidative injury and rescues Drosophila from mitochondrial defects associated with Parkinson’s Disease. In this study, we take a chemical approach to define the optimal and minimum pharmacophore responsible for the neuroprotective effects of VK. In doing so, we have developed a series of potent VK analogs with favorable drug characteristics that provide full protection at nanomolar concentrations in a well-defined model of neuronal oxidative stress. Additionally, we have characterized key cellular responses and biomarkers consistent with the compounds’ ability to rescue cells from oxidative stress induced cell death.

Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder

“…The DCFH-DA is a H 2 O 2 -sensitive fluorescence probe and can be applied to assess the intracellular H 2 O 2 40. MitoSOX Red is a live-cell permeant dye that can selectively and rapidly target mitochondria and is used to detect mitochondrial O 2 41. As shown in Figure 4B, cells stained with DCFH-DA demonstrated a significant increase in intracellular ROS production in the ASD LCLs compared with that in the control LCLs.…”

Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy

“…Compounds were delivered into mice by intraperitoneal (i.p.) injection at a dose of 100 mg/kg in sterile 5% DMSO, 95% Neobee (Josey et al, 2013). Acute toxicity was assessed by monitoring the animals for impaired neuromuscular function by placing treated mice on a rod rotating at 6 rpm.…”

“…Compounds were delivered into mice by i.p. injection at a dose of 100 mg/kg in sterile 5% DMSO, 95% Neobee (Josey et al, 2013). One of four methods for seizure induction was subsequently administered to mice at 0.25, 0.5, 1, 2 and 4 h after treatment with compound.…”

“…Our results indicated that the HDAC inhibitor NQN1 was effective at reducing seizure-related behaviors in zebrafish. The Vitamin K (VK) family shares a naphthoquinone moiety with NQN1 and recent reports have suggested that VK has a role in nervous system function (Josey et al, 2013; Ferland, 2013). We went on to show that VK3 reduced seizure-activity in zebrafish, and directed by these results, we designed, synthesized and tested new VK3 analogues.…”

Silver-Catalyzed Direct Thiolation of Quinones by Activation of Aryl Disulfides to Synthesize Quinonyl Aryl Thioethers

“…14 In all three examples, aryl, alkyl, and vinyl free radicals are generated from boronic acids, carboxylic acids, and enamides respectively under the assistance of silver, and these radicals react with thiols or disulfides to form thioethers, instead of direct activation of thiols and disulfides. With our great interest in quinone based small molecules as biologically active compounds 15 and to further expand the library of C–S coupling reactions, we report herein a silver(I)-catalyzed direct thiolation of quinones with aryl disulfides to form quinonyl aryl thioethers, in which disulfide-silver intermediates are believed to be generated to initiate the reactions under the assistance of AgOAc/(NH 4 ) 2 S 2 O 8 in DMSO at room temperature (Scheme 2, reaction 2).…”