Search Results (8)

Sphingolipids (SLs) are a class of bioactive lipids characterized by sphingoid bases (SBs) as their backbone structure. These molecules exhibit distinct cellular functions, including cell growth, apoptosis, senescence, migration, and inflammatory responses, by interacting with esterases, amidases, kinases, phosphatases, and membrane receptors. These interactions result in a highly interconnected network of enzymes and pathways, known as the sphingolipidome. Dysregulation within this network is implicated in the onset and progression of cardiovascular diseases, metabolic disorders, neurodegenerative disorders, autoimmune diseases, and various cancers. This review highlights the pharmacologically significant sphingoid-based medicinal agents in preclinical and clinical studies. These include myriocin, fingolimod, fenretinide, safingol, spisulosine (ES-285), jaspine B, D-e-MAPP, B13, and α-galactosylceramide. It covers enantioselective syntheses, drug development efforts, and advances in molecular modeling to facilitate an understanding of the binding interactions of these compounds with their biological targets. This review provides a comprehensive evaluation of chiral pool synthetic strategies, translational studies, and the pharmacological relevance of sphingolipid-based drug candidates, offering a pathway for future research in sphingolipid-based therapeutic development. Full article

Background/Objectives: Jaspine B, a synthetic analog of anhydrophytosphingosine, demonstrates significant anticancer activity; however, its clinical application is hindered by its poor oral bioavailability, resulting in suboptimal systemic exposure. This study aimed to enhance the pharmacokinetic properties of Jaspine B by developing a liposomal delivery system. Methods: Jaspine B-loaded liposomes were formulated using a microfluidic approach and characterized by transmission electron microscopy (TEM) to assess particle morphology and size distribution. A sensitive and selective LC-MS/MS assay was developed and fully validated to quantify Jaspine B in rat plasma. The assay revealed excellent linearity across a broad concentration range and high intra- and inter-day precision. A pharmacokinetic study was conducted in Sprague Dawley rats to evaluate the influence of liposomal encapsulation on the pharmacokinetic profile of Jaspine B. Results: The liposomal formulation accelerated the absorption of Jaspine B, reaching the maximum concentration (T_max) at 2 h as opposed to 6 h in plain Jaspine B. The half-life (t_1/2) increased significantly from 7.9 ± 2.3 h to 26.7 ± 7.3 h. The area under the curve (AUC_0–∞) increased over two-fold from 56.8 ± 12.3 ng.h/mL to 139.7 ± 27.2 ng.h/mL, suggesting increased systemic drug exposure. Similarly, the drug molecule’s mean residence time (MRT) increased over three-fold. Conclusions: These results indicate that liposomal formulation enhances the pharmacokinetics of Jaspine B, prolonging its body circulation and exposure, which explains the improved therapeutic outcomes we observed in our previous pharmacodynamic study. Full article

Sphingomyelin is a cell membrane sphingolipid that is upregulated in synovial sarcoma (SS). Jaspine B has been shown to inhibit sphingomyelin synthase, which synthesizes sphingomyelin from ceramide, a critical signal transducer; however, jaspine B’s low bioavailability limits its application as a promising treatment option. To address this shortcoming, we used microfluidics to develop a liposomal delivery system with increased anticancer efficacy. The nano-liposome size was determined by transmission electron microscopy. The jaspine B liposome was tested for its tumor inhibitory efficacy compared to plain jaspine B in in vitro and in vivo studies. The human SS cell line was tested for cell viability using varying jaspine B concentrations. In a mouse model of SS, tumor growth suppression was evaluated during four weeks of treatment (3 times/week). The results show that jaspine B was successfully formulated in the liposomes with a size ranging from 127.5 ± 61.2 nm. The MTT assay and animal study results indicate that jaspine B liposomes dose-dependently lowers cell viability in the SS cell line and effectively suppresses tumor cell growth in the SS animal model. The novel liposome drug delivery system addresses jaspine B’s low bioavailability issues and improves its therapeutic efficacy. Full article

Methuosis is a type of programmed cell death in which the cytoplasm is occupied by fluid-filled vacuoles that originate from macropinosomes (cytoplasmic vacuolation). A few molecules have been reported to behave as methuosis inducers in cancer cell lines. Jaspine B (JB) is a natural anhydrous sphingolipid (SL) derivative reported to induce cytoplasmic vacuolation and cytotoxicity in several cancer cell lines. Here, we have investigated the mechanism and signalling pathways involved in the cytotoxicity induced by the natural sphingolipid Jaspine B (JB) in lung adenocarcinoma A549 cells, which harbor the G12S K-Ras mutant. The effect of JB on inducing cytoplasmic vacuolation and modifying cell viability was determined in A549 cells, as well as in mouse embryonic fibroblasts (MEF) lacking either the autophagy-related gene ATG5 or BAX/BAK genes. Apoptosis was analyzed by flow cytometry after annexin V/propidium iodide staining, in the presence and absence of z-VAD. Autophagy was monitored by LC3-II/GFP-LC3-II analysis, and autophagic flux experiments using protease inhibitors. Phase contrast, confocal, and transmission electron microscopy were used to monitor cytoplasmic vacuolation and the uptake of Lucifer yellow to assess macropinocyosis. We present evidence that cytoplasmic vacuolation and methuosis are involved in Jaspine B cytotoxicity over A549 cells and that activation of 5′ AMP-activated protein kinase (AMPK) could be involved in Jaspine-B-induced vacuolation, independently of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 1 (PI3K/Akt/mTORC1) axis. Full article

This work describes the total synthesis of jaspine B involving the highly diastereoselective Pd(II)-catalysed carbonylative cyclisation in the preparation of crucial intermediates. New conditions for this transformation were developed and involved the pBQ/LiCl as a reoxidation system and Fe(CO)₅ as an in situ source of stoichiometric amount of carbon monoxide (1.5 molar equivalent). In addition, we have demonstrated the use of a flow reactor adopting proposed conditions in the large-scale preparation of key lactones. Full article

Sphingolipid metabolism is an important process in sustaining the growth needs of rapidly dividing cancer cells. Enzymes that synthesize sphingolipids have become attractive targets in cancer pharmacology. Ceramide is a precursor for synthesizing sphingolipids such as sphingomyelin, sphingosine-1-phosphate, and glucosylceramide. Sphingomyelin synthase (SMS) is the enzyme that transfers a phosphatidylcholine to ceramide to generate sphingomyelin. To test the inhibition of SMS, scientists assess the buildup of ceramide in the cell, which is cytotoxic. Because ceramide is a small lipid molecule, there are limited tools like antibodies to detect its presence. Alternatively, designated machines for small-molecule separation coupled with mass spectrometry detection can be used; however, these can be cost-prohibitive. We used a commercially available NBD-ceramide to apply to human cancer cell lines in the presence or absence of a known SMS inhibitor, jaspine B. After short incubation times, we were able to collect cell lysates and using solvent extraction methods, run the cellular material on a thin-layer chromatography plate to determine the levels of intact fluorescently labeled ceramide. Brighter fluorescence on the TLC plate correlated to greater SMS inhibition. Small molecules can then be screened quantifiably to determine the biological impact of inhibiting the sphingolipid metabolism pathways involving ceramide. Full article

We aimed to investigate the pharmacokinetics and the underlying mechanisms of the intestinal absorption, distribution, metabolism, and excretion of Jaspine B in rats. The oral bioavailability of Jaspine B was 6.2%, but it decreased to 1.6% in bile-depleted rats and increased to 41.2% (normal) and 23.5% (bile-depleted) with taurocholate supplementation (60 mg/kg). Consistent with the increased absorption in the presence of bile salts, rat intestinal permeability of Jaspine B also increased in the presence of 10 mM taurocholate or 20% bile. Further studies demonstrated that the enhanced intestinal permeability with bile salts was due to increased lipophilicity and decreased membrane integrity. Jaspine B was designated as a highly tissue-distributed compound, because it showed large tissue to plasma ratios in the brain, kidney, heart, and spleen. Moreover, the recovery of Jaspine B from the feces and urine after an intravenous administration was about 6.3%, suggesting a substantial metabolism of Jaspine B. Consistent with this observation, 80% of the administered Jaspine B was degraded after 1 h incubation with rat liver microsomes. In conclusion, the facilitated intestinal permeability in the presence of bile salts could significantly increase the bioavailability of Jaspine B and could lead to the development of oral formulations of Jaspine B with bile salts. Moreover, the highly distributed features of Jaspine B in the brain, kidney, heart, and spleen should be carefully considered in the therapeutic effect and toxicity of this compound. Full article

A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. Full article