The Effect of FTY720 on Sphingolipid Imbalance and Cognitive Decline in Aged EFAD Mice.

Background: During Alzheimer's disease (AD) progression, there is a decline in the bioactive sphingolipid sphingosine-1-phosphate (S1P). Previous research showed that FTY720, an S1P mimetic, prevented cognitive decline and reduced ceramide levels in transgenic mice with familial AD carrying the human APOE4 gene (E4FAD) at 6-7 months of age.

Objective: The objective of this study is to explore the protective effects of FTY720 at late-stage AD.

Total Synthesis of Hemerocallisamine I Paved by Gram-Scale Synthesis of (2,4)-4-Hydroxyglutamic Acid Lactone.

Total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is presented, both in racemic and enantiopure form. Our synthetic strategy involves (2,4)-4-hydroxyglutamic acid lactone as the key intermediate. Starting from an achiral substrate, the target stereogenic centers were introduced by means of crystallization-induced diastereomer transformation (CIDT) in a highly stereoselective fashion.

Synthesis and structure-activity relationship of berkeleylactone A-derived antibiotics.

Berkeleylactone A is a potent 16-membered macrolactone antibiotic, recently isolated from a coculture of Berkeley Pit Lake fungi. Although its antimicrobial activity has already been investigated, little is known about the structure-activity relationship. Based on our previous synthetic studies, a series of berkeleylactone A derivatives were synthesized and evaluated for their antimicrobial activities against methicillin-sensitive and methicillin-resistant (MRSA) strains.

FTY720 decreases ceramides levels in the brain and prevents memory impairments in a mouse model of familial Alzheimer's disease expressing APOE4.

The protection mediated by the bioactive sphingolipid sphingosine-1-phosphate (S1P) declines during Alzheimer's disease (AD) progression, especially in patients carrying the apolipoprotein E ε4 (APOE4) isoform. The drug FTY720 mimics S1P bioactivity, but its efficacy in treating AD is unclear. Two doses of FTY720 (0.

Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles.

The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non-vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites.

Stereochemical switch driven by crystallization: Interplay between stoichiometry and configuration of the products.

An intriguing example of a crystallization-induced stereochemical switch in the configuration of aza-Michael reaction products is described. Depending on both the stereochemical purity and stoichiometric ratio of the chiral amine used, the reaction delivers crystalline diastereomers of a different stereochemistry. The optically pure diastereomer smoothly converts to its racemic epimer salt upon the addition of a complementary chiral amine.

Antibacterial Electrospun Polycaprolactone Nanofibers Reinforced by Halloysite Nanotubes for Tissue Engineering.

Due to its slow degradation rate, polycaprolactone (PCL) is frequently used in biomedical applications. This study deals with the development of antibacterial nanofibers based on PCL and halloysite nanotubes (HNTs). Thanks to a combination with HNTs, the prepared nanofibers can be used as low-cost nanocontainers for the encapsulation of a wide variety of substances, including drugs, enzymes, and DNA.

Visible-Light-Promoted Cross-Coupling of -Alkylpyridinium Salts and Nitrostyrenes.

A stereoselective, denitrative cross-coupling of β-nitrostyrenes with -alkylpyridinium salts for the preparation of functionalized styrenes has been developed. The visible-light-induced reaction proceeds without any catalyst at ambient temperature. Broad in scope and tolerant to multiple functional groups, the moderately yielding transformation is orthogonal to several traditional metal-catalyzed cross-couplings.

CERT reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease.

Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains.

Ceramide analog [F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer's disease transgenic mice by functioning as a metabolic probe.

The metabolism of ceramides is deregulated in the brain of Alzheimer's disease (AD) patients and is associated with apolipoprotein (APO) APOE4 and amyloid-β pathology. However, how the ceramide metabolism changes over time in AD, in vivo, remains unknown. Distribution and metabolism of [F]F-HPA-12, a radio-fluorinated version of the ceramide analog N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, was investigated in the brain of AD transgenic mouse models (FAD) on an APOE4 or APOE3 genetic background, by positron emission tomography and by gamma counter.

Crystallization Does It All: An Alternative Strategy for Stereoselective Aza-Henry Reaction.

An efficient and experimentally straightforward method for the stereoselective synthesis of a variety of β-nitro-α-amino carboxylic acids via aza-Henry (nitro-Mannich) reaction of aldimines is disclosed, yielding either anti- or a rarely reported syn-configuration. The reaction operates directly on free glyoxylic acid and generates imine species in situ. Crystallization-controlled diastereoselectivity enables isolation of the target compounds in high enantio- and diastereomeric purities by a simple filtration.

Total Synthesis of Berkeleylactone A.

The first total synthesis of the potent antibiotic berkeleylactone A is described in 10 steps with an overall yield of 9.5%. A key step of our concise route is a late-stage, highly diastereoselective, sulfa-Michael addition.

Stereoselective Synthesis of Functionalized α-Amino Acids Isolated by Filtration.

Crystallization-induced diastereomer transformation (CIDT) represents a highly appealing and convenient synthetic tool. Despite its numerous advantages, it remains rather rarely used due to its uncertain predictability to occur. Herein, we describe CIDT based on aza-Michael reactions of diversely functionalized ( E)-3-acylacrylic acids.

Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions.

One main mechanism of insulin resistance (IR), a key feature of type 2 diabetes, is the accumulation of saturated fatty acids (FAs) in the muscles of obese patients with type 2 diabetes. Understanding the mechanism that underlies lipid-induced IR is an important challenge. Saturated FAs are metabolized into lipid derivatives called ceramides, and their accumulation plays a central role in the development of muscle IR.

Development and Optimization of a High-Throughput Screening Assay for Rapid Evaluation of Lipstatin Production by Streptomyces Strains.

Pancreatic lipase inhibitors, such as tetrahydrolipstatin (orlistat), are used in anti-obesity treatments. Orlistat is the only anti-obesity drug approved by the European Medicines Agency (EMA). The drug is synthesized by saturation of lipstatin, a β-lactone compound, isolated from Streptomyces toxytricini and S.

Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications.

Ceramide levels are increased in blood and brain tissue of Alzheimer's disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking.

Interaction between the PH and START domains of ceramide transfer protein competes with phosphatidylinositol 4-phosphate binding by the PH domain.

synthesis of the sphingolipid sphingomyelin requires non-vesicular transport of ceramide from the endoplasmic reticulum to the Golgi by the multidomain protein ceramide transfer protein (CERT). CERT's N-terminal pleckstrin homology (PH) domain targets it to the Golgi by binding to phosphatidylinositol 4-phosphate (PtdIns(4)P) in the Golgi membrane, whereas its C-terminal StAR-related lipid transfer domain (START) carries out ceramide transfer. Hyperphosphorylation of a serine-rich motif immediately after the PH domain decreases both PtdIns(4)P binding and ceramide transfer by CERT.

Chemistry and Biology of HPAs: A Family of Ceramide Trafficking Inhibitors.

In 2001, two years before the disclosure of the CERT-associated Cer transfer machinery, N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)alkanamides (HPAs) were described as the first, and to date unique, family of intracellular Cer trafficking inhibitors. The dodecanamide derivative, HPA-12, turned out to be a benchmark as a cellular inhibitor of CERT-mediated de novo sphingomyelin biosynthesis. In only 15 years after its first disclosure, this compound has prompted a growing number of biological and chemical studies.

Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT.

A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences.

Identification of novel CERT ligands as potential ceramide trafficking inhibitors.

A highly compartmentalized enzymatic network regulates the pro-apoptotic and proliferative effects of sphingolipids. Over-conversion of ceramide (Cer) correlates with insensitivity to apoptosis signaling (in response to chemotherapy) and to drug resistance of cancer cells. De novo sphingomyelin biosynthesis relies on non-vesicular ceramide trafficking by the CERT (CERamide Transfer) protein.

Expedient and practical synthesis of CERT-dependent ceramide trafficking inhibitor HPA-12 and its analogues.

The practical stereodivergent route to both syn- and anti-diastereomers of 1-substituted 3-aminobutane-1,4-diols based on the crystallization-induced asymmetric transformation (CIAT) approach was completed. This led to the revision of the reported stereochemistry of the first inhibitor of CERT-dependent ceramide trafficking HPA-12 from (R,R)-anti- to the (R,S)-syn-enantiomer. Due to the expeditiousness of production and inexpensive conditions developed, a series of alkyl- and aryl-substituted analogues of HPA-12 is also reported.

CIAT with simultaneous epimerization at two stereocenters. Synthesis of substituted beta-methyl-alpha-homophenylalanines.

Diastereoselective aza-Michael additions of phenylethylamine to 3-aroylbutenoic acids are reported. During these processes, efficient control over two new stereogenic centers on the Michael acceptor has been possible via crystallization-induced asymmetric transformation (CIAT). As an application, a convenient two-step synthesis of anti-beta-methylhomophenylalanines is also described.