ABSTRACT
A total synthesis of echinodermatous ganglioside LLG-3 with neuritogenic activity was accomplished by a convergent strategy. The synthesis of 2-hydroxyethyl 8-O-Me-α-sialoside 2 was started from the phenyl 7,8-di-O-Pico-thiosialoside 5, which can be chemoselectively removed the picoloyl group, and then the methyl group in 8-O-MeNeu5Ac moiety was chemoselectively prepared using TMSCHN2/FeCl3. For preparation of the terminal disialic unit, oxidative amidation was initially utilized by our group to efficiently construct the α(2,11) linkage of 8-O-Me-Neu5Acα(2,11)Neu5Gc. Herein, we also demonstrate that the synthesized ganglioside LLG-3 exhibited the neuritogenic activity toward the primary cortical neurons and that biological activity is superior to that of ganglioside DSG-A.
Subject(s)
Gangliosides/chemical synthesis , Gangliosides/pharmacology , Neurons/chemistry , Animals , Glycosylation , Molecular Structure , Neuronal Outgrowth/physiology , PC12 Cells , RatsABSTRACT
Alzheimer's disease (AD) is characterized by extracellular deposition of amyloid plaques, which are predominantly composed of amyloid-ß (Aß) peptide derived from amyloid precursor protein (APP) cleavage. APP interacts with tropomyosin receptor kinase A, a neurotrophic receptor associated with gangliosides and mediating neuronal survival and differentiation through the extracellular signal-regulated protein kinase (ERK) pathway. The ganglioside Hp-s1's analogue Hp-s1A exerts neuritogenic activity; however, its effect on AD pathology remains unknown. To test the hypothesis that Hp-s1A is a potential candidate to treat AD, we established the AD-modeled cell line by expressing human Swedish and Indiana APP gene (APP-Swe/Ind) in N2a mouse neuroblastoma cells. The cells were treated with Hp-s1A or monosialoganglioside GM1 for comparison. The AD model cells expressing APP-Swe/Ind exhibited a significant reduction in viability, as well as neurite outgrowth rate, in comparison to the control cells expressing APP-695. APP C-terminal fragment-ß (CTFß) and Aß42 were increased in the AD cell lysates and the culture media, respectively. With the treatment of either Hp-s1A or GM1 at 1 µM, the AD model cells showed a significant increase in viability; however, only Hp-s1A reduced CTFß levels in these cells. Further analysis of the culture media revealed that Hp-s1A also reduced Aß42 production from AD model cells. The phosphorylation of ERK was elevated and the neurite outgrowth rate was restored with Hp-s1A treatment. In conclusion, the ganglioside analogue Hp-s1A inhibited amyloidogenic processing of APP and promoted neurotrophic activity and survival of AD model cells. Hp-s1A has great potential in AD therapeutic development.
Subject(s)
Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Gangliosides/pharmacology , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/drug effects , Animals , Cell Survival/drug effects , Disease Models, Animal , Extracellular Signal-Regulated MAP Kinases/metabolism , Gangliosides/metabolism , Humans , Mice , Neurons/drug effects , Neurons/metabolism , Peptide Fragments/drug effects , Peptide Fragments/metabolism , Plaque, Amyloid/drug therapy , Plaque, Amyloid/metabolism , Presenilin-1/geneticsABSTRACT
An efficient α-sialylation method for many primary hydroxyl acceptors that include 6-OH glycosides has been developed. 7,8-Di-O-picoloyl sialyl glycoside was used as the glycosyl donor, and α-glycoconjugation was controlled by using the 7,8-di-O-picoloyl moiety in CH2Cl2. The methodology was successfully applied to the total synthesis of ganglioside Hp-s1 possessing neuritogenic activity.
ABSTRACT
The first total synthesis of ganglioside DSG-A (1) is achieved via chemoselective glycosylation and a [1 + 1 + 2] synthetic strategy. We have also developed an efficient method that can be handled on large scale (50 g) for the synthesis of the phytosphingosine.
Subject(s)
Gangliosides/chemical synthesis , Sphingosine/analogs & derivatives , Animals , Gangliosides/pharmacology , Glycosylation , Neurites/drug effects , PC12 Cells , Rats , Sphingosine/chemical synthesisABSTRACT
We propose a facile approach toward enhancing the efficiency of fluoride-responsive gels through the positioning of functionalized receptor units, allowing tunable intra- and intermolecular hydrogen bonding, in the gelator molecules. We prepared the new glycolipid-based gelator 2 and its hydroxy and methoxy derivatives 2a and 2b, respectively, to study the effects of three types modes of supramolecular assembly: solely intermolecular hydrogen bonding in 2, solely intramolecular hydrogen bonding in 2b, and both inter- and intramolecular hydrogen bonding in 2a. 1H NMR spectra confirmed the self-assembly interactions of these glycolipid-based gelators. We measured the minimum gel concentrations and sol-gel transitions and recorded X-ray diffraction patterns and electron micrographs to characterize the gelation behavior and structural organization of each of these supramolecular gels. Among these three gelators, only 2 and 2a could form organogels in the test solvents, indicating that intermolecular hydrogen bonding plays a determinant role in the supramolecular assemblies leading to gelation. The self-assembly of 2 resulted in a bilayer-packed lamellar structure within ribbon-like fibers, whereas that of 2a resulted in hexagonally packed cylindrical micelles within tree-like fibers. A minimum amount of 0.3 equivalent of F- was required for complete disruption of the gel formed from 2a, which was approximately four times lower than that required for the gel formed from 2. Thus, the incorporation of a ß-hydroxy motif-the only difference in the chemical structures of 2 and 2a-led to interesting variations in the resulting gel morphologies and enhanced the gel's fluoride-responsiveness.
