Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

Abstract

With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and Aβ1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD.

Occurrence of Morpholine in Central Nervous System Drug Discovery

“…The replacement of the piperidine scaffold with a morpholine ring in a previous series of compounds resulted in an overall improvement of potency and CYP3A4 liability (see compound 19 in Figure a). The introduction of morpholine was found beneficial also in a class of C-glucosyl chromen-4-ones, as the p -morpholinyl flavone 21 stood out for its ability to interact with Aβ42 peptides, reducing Aβ42-induced cell death in AD and neuroblastoma model systems (Figure b) …”

“…The introduction of morpholine was found beneficial also in a class of C-glucosyl chromen-4-ones, as the p-morpholinyl flavone 21 stood out for its ability to interact with Aβ42 peptides, reducing Aβ42-induced cell death in AD and neuroblastoma model systems (Figure 13b). 98 Finally, another molecular target that has been recently proposed due to its involvement in the amyloid cascade is δsecretase, also known as asparagine endopeptidase (AEP) or legumain. 99 This lysosomal cysteine proteinase cleaves both amyloid precursor protein (APP) and tau, two major pathogenic players in AD.…”

Neuroprotective activities of bacopa, lycopene, astaxanthin, and vitamin B12 combination on oxidative stress‐dependent neuronal death

“…Vitamin B12 is a coumarin class of compounds with different physiological and pharmacological effects, comprising antibacterial, antioxidant, anti‐inflammatory 18 . In a previous study the neuroprotective activity of vitamin B12 versus H 2 O 2 ‐induced neuronal cell injury in SH‐SY5Y cells undifferentiated was shown 19 . This cell line was pretreated with different doses (0.2‐200 μM) of vitamin B12 for 12 hours, followed by exposure to 200 μM of H 2 O 2 for another 24 hours.…”

Recent Advances in the Development and Synthesis of Carbohydrate‐Based Molecules with Promising Antibacterial Activity

“…These observations are generally consistent with other reports. [9,11] The synthesis of both compounds 15 and 16 started from d-xylose (17, Scheme 2). After conversion into the thermodynamically preferred diacetone-d-xylofuranose (18) when in the presence of acetone, copper sulfate, and sulfuric acid, the selective removal of the acetal moiety in positions 3 and 5 after treatment with a 0.2 % aqueous solution of HCl gave monoacetonide 19.…”

“…[4] On top of being inexpensive and easily accessible, sugars are multifunctional, synthetically versatile, stereochemically rich, and naturally bioactive; henceforth, they have been used in the synthesis of bioactive glycomimetics and glycoconjugates, offering unique opportunities for the establishment of multivalent interactions with molecular targets of therapeutic interest. [4][5][6] In fact, several glycoconjugates have been shown to display enhanced pharmacological potency and lower cytotoxicity when compared to their aglycones, [7][8][9] and many have exhibited improved water solubility and bioavailability profiles. [10][11][12] Moreover, C-glucosyl moieties have been found to positively modulate the Pan-Assay Interference CompoundS (PAINS)-type behavior of membrane-disrupting lipophilic polyphenols, further highlighting the importance of glyco-based scaffolds in medicinal chemistry.…”