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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
31

A sphingosine-1-phosphate receptor type 1 agonist, ASP4058, suppresses intracranial aneurysm through promoting endothelial integrity and blocking macrophage transmigration / スフィンゴシン1-リン酸受容体1アゴニストASP4058は血管内皮の健全性を高めマクロファージの経内皮浸潤を阻害することによって脳動脈瘤の形成を抑制する

Yamamoto, Rie 26 March 2018 (has links)
京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13167号 / 論医博第2154号 / 新制||医||1029(附属図書館) / (主査)教授 宮本 享, 教授 小泉 昭夫, 教授 柳田 素子 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM
32

Antagonist of sphingosine 1-phosphate receptor 3 reduces cold injury of rat donor hearts for transplantation / スフィンゴシン1リン酸受容体3の阻害剤はラット心臓移植における冷保存時のグラフト障害を軽減する

Kanemitsu, Eisho 23 March 2023 (has links)
京都大学 / 新制・論文博士 / 博士(医学) / 乙第13535号 / 論医博第2275号 / 新制||医||1065(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 湊谷 謙司, 教授 小林 恭 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM
33

Fused Heterocycles as Spinster Homolog 2 Inhibitors and Regio- and Stereoselective Copper-Catalyzed Borylation-Protodeboronation of 1,3-Diynes: Access to (Z)-1,3-Enynes

Burgio, Ariel Louise 15 May 2023 (has links)
Sphingosine 1-phosphate (S1P) is a lipid chemoattractant molecule. Once formed, S1P can be transported extracellularly by S1P transporters spinster homolog 2 (Spns2) or major facilitator domain containing 2B (mfsd2b). In the extracellular space, S1P can bind to S1P-specific G-protein coupled receptors (S1PR), which initiate many signaling pathways. A critical role of extracellular S1P is its ability to cause lymphocyte egress, which can have implications for inflammatory and autoimmune diseases. For this reason, there has been a growing interest in exploring potential spns2 inhibitors to further elucidate their therapeutic potential. Initial screenings confirmed that fused heterocycles, including phthalimide and benzoxazoles, demonstrated moderate inhibition of Spns2 using a HeLa cell assay. An extensive structure-activity relationship (SAR) study of these scaffolds was performed to analyze the impact of various amine head groups, regioisomers, and alkyl tails on performance. It was determined that 2-aminobenzoxazoles with secondary amines were potent inhibitors of the transporter. Additionally, the position of the lipophilic tail moiety played a large role in activity. From these modifications, SLB1122168 (2.44p) was found to be our lead compound. It was determined that (2.44p) had an IC50 of 94 ± 6 nM and was shown to be efficacious in decreasing lymphocyte count by 55% in a dose-dependent manner in both rat and mice models. The discovery of (2.44p) can serve as a novel chemical tool to investigate Spns2 biology and use it as a probe to determine the potential of Spns2 as a drug target. Organoboron compounds are useful synthetic intermediates in forming C-X, C-C, and C-H bonds. One way to synthesize these compounds is through copper catalysis. Copper is favorable to other transition metals because it is an Earth-abundant, low-cost metal that can be utilized in regio- and stereoselective reactions. Conjugated 1,3-enynes are important functional groups that iii are found in active natural products, organic synthetic intermediates, and materials. Previous methods used rare transition metals, designer ligands, or harsh acidic conditions to synthesize such compounds. In this dissertation, we developed a stereoselective one-pot copper-catalyzed semi-reduction of 1,3-diynes to produce (Z)-1,3-enynes. This method uses Cu(OAc)2, HBpin and Xantphos to successfully synthesize (Z)-1,3-enynes that were tolerated well over a broad substrate scope, including heterocyclic, alkyl, and aryl substituents. It was determined that this reaction went through a 2-boryl intermediate which was facilitated by a CuH species. / Doctor of Philosophy / Autoimmune diseases are caused by immune cells attacking healthy cells. The signaling lipid sphingosine-1-phosphate (S1P) plays a major role in trafficking immune cells, in which immune cells follow the S1P gradient from low concentrations (secondary lymphoid tissues) to high concentrations (lymph). In the case of multiple sclerosis, immune cells can attack healthy neurons that cause a myriad of symptoms. Currently, there are four drugs approved by the Food and Drug Administration (FDA) targeting the S1P pathway for multiple sclerosis. In all cases, these drugs act as S1P-receptor (S1PR) functional antagonists, which decreases the amount of extracellular S1P, which in turn decreases the immune cells in the lymph that can attack healthy cells. Unfortunately, all four drugs exhibit on-target cardiovascular side effects. To circumvent the on-target side effects seen in current FDA-approved drugs, other nodes of the S1P pathway have been assessed for multiple sclerosis. One node of interest is spinster homolog 2 (Spns2), a transporter of S1P, whose inhibition has also been shown to decrease extracellular S1P. In this dissertation, we will be assessing various inhibitors for their in vitro and in vivo properties. 1,3-Enynes are a functional group found in medicinally relevant compounds and can be used as intermediates to make more complex compounds. Current methods to make this functional group use expensive rare metals or harsh acidic conditions. We developed new methods that utilized copper, an abundant metal, and boron, an atom whose empty p orbital allows for unique reactivity. Utilizing a copper-hydride species allowed us to semi-reduce 1,3-diynes to (Z)-1,3-enynes, where water was used instead of acid to allow for the semi-reduction to occur. This reaction was shown to tolerate a wide range of substrates and gave good to excellent yield.
34

Developing Sphingosine-1-Phosphate (Spns2) Inhibitors for the Treatment of Multiple Sclerosis

Shrader, Christopher Wayne 29 February 2024 (has links)
Doctor of Philosophy / Autoimmune diseases are caused when a person's immune system attacks its own healthy cells. In a person with multiple sclerosis, their immune system becomes sensitized to the myelin sheath that covers their neurons in the central nervous system. This results in the degradation of the myelin sheath and irreversible degradation of the nerve cell axons. This damage leads to the development of several neurological impairments, such as pain, fatigue, mobility problems, and numbness. While there is no cure for multiple sclerosis, disease-modifying therapies are typically taken by patients to suppress their immune system and slow disease progression. Sphingsoine-1-phosphate (S1P) is a lipid that is important for the trafficking of lymphocytes into a person's central nervous system. This trafficking is largely due to the natural gradient of S1P which is high levels in blood but low in tissues. Lymphocytes will follow this gradient from areas of low S1P concentration (lymphatic tissue) to areas with higher S1P concentrations. Modulation of S1P levels is the mechanism of action for several FDA approved drugs as they target primarily S1P1 receptors to achieve lower levels of circulating lymphocytes. However, targeting this receptor also results in cardiovascular side effects such as first-dose bradycardia. The transporter for S1P, spinster homolog 2 (Spns2), which is upstream of the S1P receptors, is another viable target that our lab has recently been targeting. Spns2 inhibition decreases extracellular S1P levels and result in reduced lymphocytes in mice models. In this dissertation, several inhibitors were developed and assessed for their in vitro and in vivo ability to inhibit Spns2.
35

Development of Potent Inhibitors of the Sphingosine-1-Phosphate Transporter Spns2 for the Treatment of Multiple Sclerosis

Foster, Daniel John 07 July 2022 (has links)
Sphingosine-1-phosphate (S1P) is an amino-alcohol signaling molecule produced from the intracellular phosphorylation of the lipid sphingosine. Despite possessing several identified intracellular targets, the predominant signaling functionality of S1P is derived from its activation of membrane-bound G-protein coupled receptors (GPCRs). The binding of S1P to these receptors (S1P1-5) is closely associated with immune cell development and recruitment. As such, the modulation of S1P-related pathways is of particular interest for the development of immunomodulating agents. To reach its native GPCRs, S1P must be released from the cell. This process is facilitated by the transmembrane transport protein Spinster homolog 2 (Spns2) in most vertebrates. Studies in murine species have demonstrated that the protein plays a key role in directing immune cell chemotaxis and the progression of autoimmune diseases. Consequently, Spns2 represents an attractive target for the pharmaceutical induction of immunosuppression. While several drugs that act through the modulation of S1P receptor signaling have received FDA approval for the treatment of autoimmune disorders (fingolimod, siponimod, ozanimod, and ponesimod), they typically manifest on-target cardiovascular side-effects. Therefore, the development of novel Spns2 inhibitors is a prudent alternative approach to achieve S1P-mediated lymphopenia. In this dissertation, the design, synthesis, and activities of highly potent Spns2 inhibitors are disclosed. These structures spanned several scaffolds and culminated in the discovery of a phenylurea derivative 4.11i. In vitro assessment of 4.11i demonstrated that the compound possessed an IC50 value of 92 nM, making it the most potent inhibitor of Spns2 disclosed to date. Intraperitoneal administration of 4.11i (10 mg/kg dose) into mice reduced circulating lymphocyte counts and impaired the progression of experimental autoimmune encephalomyelitis (a murine model of multiple sclerosis). Taken together, these data validated the target of 4.11i in vivo and represented the first reported instance of Spns2 inhibition as a viable multiple sclerosis treatment. Additional work is currently being undertaken to further improve in vivo activity and pharmacokinetic properties of 4.11i. / Doctor of Philosophy / White blood cells comprise a significant portion of the body's natural defense mechanisms. In healthy individuals, these white blood cells identify and destroy foreign materials and organisms. However, in patients with multiple sclerosis, immune cells can become sensitized to protein fragments lining the myelin sheath of neurons. These autoreactive immune cells recognize the body's natural neuronal proteins as antigens. Damage exerted by autoreactive cells leads to the development of neurological impairments (i.e., fatigue, muscle weakness, and slurred speech) as nerve impulses are disrupted before reaching their target. First-line treatment of multiple sclerosis often centers on the administration of immunosuppressive drugs to curtail the progression of the disease and mitigate immune cell-directed demyelination. A driving factor in white blood cell localization is the lipid sphingosine-1-phosphate (S1P). Concentrations of S1P are often not static in the body, with different tissue types and fluids possessing variable levels. Immune cells, and lymphocytes in particular, use this natural S1P gradient to dictate their movement within the body. Lymphocytes will track with the S1P gradient, going from areas of lower S1P concentration (lymph tissue) to areas of higher S1P concentration where synthetic enzyme expression is upregulated (multiple sclerosis lesions). Consequently, the development of drugs that can alter this S1P gradient represents an ideal avenue to achieve immunosuppression. One key mediator of S1P release is the transmembrane transport protein Spinster homolog 2 (Spns2). This protein directs the secretion of intracellular S1P into the extracellular space and is necessary for lymphocytes to enter circulation. However, little effort has been devoted to the development of Spns2 inhibitors. As such, the inhibition of this protein represents a novel and underexplored target for the treatment of autoimmune disorders. In this disclosure, the structures of several highly potent Spns2 inhibitors are revealed. The work around these structures led to the discovery of 4.11i. This compound proved highly potent in biological assays and animal models. Mice treated with 4.11i experienced a reduction in circulating lymphocyte counts and demonstrated less symptom manifestation in multiple sclerosis disease models.
36

Design and Synthesis of Orally Bioavailable Sphingosine Kinase 2 Selective Inhibitors

Sibley, Christopher David 16 July 2020 (has links)
In humans, mammals, and perhaps all vertebrates, sphingolipids exist as a family of cellular signaling molecules and have been shown to be involved in a wide range of biological processes ranging from proliferation to apoptosis. As such, sphingolipid signaling has garnered the attention of numerous researchers as an attractive candidate for pharmacological manipulation. The synthetic pathway of one prominent sphingolipid, sphingosine 1-phosphate (S1P), has been implicated in a variety of disease states such as cancer, sickle cell disease, multiple sclerosis, and renal fibrosis. Formation of S1P is facilitated from the ATP dependent phosphorylation of sphingosine (Sph) through its generative enzyme's sphingosine kinase 1 and 2 (SphK1 and SphK2). Inhibition of SphK1 and SphK2 results in the manipulation of S1P levels, which has been shown to be therapeutic in various animal models of disease. While there are multiple examples of potent SphK1-selective and dual SphK1/2 inhibitors, SphK2-selective inhibitors are scarce. Herein, we describe the design, synthesis and biological testing of SphK2-selective inhibitors. We first describe the discovery that introducing a trifluoromethyl group onto the internal aryl ring of our inhibitor scaffold led to superior selectivity and potency towards SphK2. We demonstrate that the trifluoromethyl moiety is interacting with a previously unknown side cavity in the substrate binding site of SphK2 that is unique and could be exploited in the design of SphK2-selective inhibitors. The synthesis of 21 derivatives with various substituents spanning off the internal aryl ring was completed, therefore characterizing the preferred size and chemical nature of moieties positioned in that portion of the binding site. This work led to the development of the most potent SphK2-selective inhibitor known at the time. We then describe the transformation of our SphK2-selective inhibitors into an orally bioavailable drug. We explain how the guanidine functionality on our inhibitor scaffold hinders our compounds from being orally bioavailable. Consequently, a library of 24 derivatives with various modifications to the guanidine functionality was synthesized and evaluated for improved orally bioavailability. Highlighted in this work is the development of the most potent SphK2-selective inhibitor currently known 3.14 (SLS1081832), which displays a hSphK2 Ki of 82 nM and 122-fold selectivity for SphK2. Chemical modification and in vivo assessment of 3.14 (SLS1081832) prodrugs was explored. / Doctor of Philosophy / In humans, sphingosine 1-phosphate (S1P) is a signaling molecule that is generated through an ATP dependent reaction of sphingosine (Sph) via sphingosine kinase 1 and 2 (SphK1 and SphK2). Furthermore, S1P has been shown to be implicated in various diseases such as cancer, sickle cell disease, multiple sclerosis, and renal fibrosis. Inhibition of SphK1 and SphK2 has been shown to be therapeutic towards the symptoms of these diseases. Therefore, in order to alleviate these disorders, the concentrations of S1P must be controlled through pharmacological inhibition of SphK1 and SphK2. There are multiple reported examples of potent SphK1-selective and dual SphK1/2 inhibitors; however, SphK2-selective inhibitors are scarce. This work describes the synthesis and biological assessment of 21 compounds for their effectiveness in selectively targeting and inhibiting SphK2. The work led to the discovery of a previously unrecognized side cavity in the binding pocket of SphK2 that enhances inhibitor potency and selectivity towards SphK2. Furthermore, studies characterizing the preferred size and chemical nature of moieties positioned in that portion of the binding site led to the development of the most potent SphK2- selective inhibitor known at the time. Building on this work, we next focused on the transformation of our SphK2-selective inhibitors into a drug that could be administered orally. We describe the synthesis of 24 compounds with various modifications to one portion of our scaffold and their effect on improved orally bioavailability. This work led to the development of the most potent SphK2-selective inhibitor currently known 3.14 (SLS1081832).
37

Structure Activity Relationship Studies on Isoform Selective Sphingosine Kinase Inhibitors

Congdon, Molly D. 23 August 2016 (has links)
A variety of diseases including Alzheimer's disease, asthma, cancer, fibrosis, multiple sclerosis, and sickle cell disease have been associated with elevated levels of sphingosine-1-phosphate (S1P). S1P, a pleiotropic lipid mediator involved in a broad range of cellular processes, is synthesized solely by the phosphorylation of sphingosine (Sph) and is catalyzed by the two isoforms of sphingosine kinase (SphK1 and SphK2). Therefore, SphKs are a potential therapeutic target; however, the physiological role of SphK2 is still emerging. In order to determine the role of SphK2 in vivo, more potent and selective small molecule inhibitors of SphK2, as well as dual inhibitors are necessary. Herein, explorations and advancements on the second generation SphK2 selective inhibitor SLR080811 are disclosed. Investigations into the lipophilic tail region of the hSphK2 inhibitor SLR080811 are detailed. This investigation highlights the dependency of SphK2 selectivity and potency on overall compound length. More importantly, this study identified the internal aryl ring of SLR080811 as a key pharmacophore of the scaffold. To further probe the significance of the aromatic region, the phenyl ring was replaced by a 2,6-naphthyl ether skeleton. Investigations into the tail region of this scaffold are described in detail. Key discoveries from this structure-activity relationship study include SLC5111312 (hSphK2 Ki = 0.90 μM, dual hSphK inhibitor), SLC5091592 (hSphK2 Ki = 1.02 μM, > 20-fold hSphK2 selective) and SLC5121591 (hSphK2 Ki = 0.61 μM, >16-fold hSphK2 selective). Molecular modeling studies with hSphK2 indicate that the extended aromatic group is able to participate in π-π stacking interactions with Phe548. In silico docking studies indicate that a guanidine hydrogen bond to Asp211 is key for SphK2 selectivity, and incorporation of a 3'-hydroxyl group on the pyrrolidine ring increases hydrogen bonding to Asp308, thereby increasing SphK1 potency and reducing selectivity. Additionally, biological studies employing SLC5111312 have helped to further elucidate the role of SphK2, suggesting that SphK2 has a catalytic role in the regulation of blood S1P levels. The shape of the hSphK2 binding pocket was probed by introducing an indole moiety in place of the naphthyl ring and varying its substitution pattern. One key discovery from this study is SLC5101465 (hSphK2 Ki = 0.09 μM, > 111 fold SphK2 selective), which has a 1,5-indole substitution pattern with an N-nonyl "tail". Molecular docking simulations highlight the importance of rotatable bonds and a relatively linear orientation between the "head group" and "tail group" to maintain essential hydrogen bond interactions to Asp residues with the guanidine moiety while minimizing steric interactions in the middle of the binding pocket. Expanding upon the 1,5-indole scaffold of SLC5101465, a series of aryl tail derivatives are examined. This study confirms the necessity of electron withdrawing groups located at the end of the inhibitor scaffold to optimize binding in the tail region of the SphK2 binding pocket. / Ph. D.
38

Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors

Raje, Mithun 08 June 2012 (has links)
Sphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell proliferation. SphK phosphorylates sphingosine to form sphingosine-1-phosphate (S1P) which has been implicated as a major player in cancer growth and survival. SphK exists as two different isoforms, namely SphK1 and SphK2, which play different roles inside the cell. The dearth of isoenzyme-selective inhibitors has been a stumbling block for probing the exact roles of these two isoforms in disease progression. This report documents our efforts in developing SphK2-selective inhibitors. We provide the first demonstration of a SphK inhibitor containing a quaternary ammonium salt. We developed highly potent and moderately selective inhibitors that were cell permeable and interfered with S1P signaling inside the cell. In an effort to improve the selectivity of our inhibitors and enhance their in vivo stability, we designed and synthesized second generation inhibitors containing a heteroaromatic linker and a guanidine headgroup. These inhibitors were more potent and selective towards SphK2 and affected S1P signaling in cell cultures and various animal models. / Ph. D.
39

Structure-activity relationship studies and biological evaluation of selective sphingosine kinase inhibitors

Morris, Emily A. 01 June 2015 (has links)
Sphingosine 1-phosphate (S1P) has become a prevalent drug discovery target due to studies implicating it to several disease pathologies such as fibrosis, sickle cell disease, inflammation, diabetes, and cancer. S1P functions to induce cell proliferation and migration. S1P signaling occurs through intracellular targets or transport outside of the cell via ABC transporters, where it acts as a ligand to G-protein coupled receptors (S1P1-5). Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to S1P; these are the only enzymes known to mediate the phosphoryl transfer. Inhibiting either or both SphKs helps to modulate S1P, which may be useful as a therapeutic avenue for disease states where S1P signaling has gone awry. Herein, we document our efforts in profiling the structure-activity relationships (SAR) of SphK2 through an iterative process of synthesis and biological testing. First, an SAR structured around the head and linker region of our lead molecule, SLR080811, was performed. SLR080811 has a Ki of 1.3 µM and is 5-fold selective for SphK2. The modifications performed on SLR080811 yielded two promising inhibitors: SLP120701 (SphK2 selective with a Ki of 1.2 µM) and SLP7111228 (>200 fold selective for SphK1 with a Ki of 48 nM). In vitro studies in U937 cells yielded a decrease in S1P levels with the introduction of inhibitors. Mouse studies provided insight into the pharmacokinetic effect of our SphK2-selective inhibitors, revealing an increase in S1P levels in the blood. When in vivo studies were performed with the SphK1 selective inhibitor, S1P levels in blood decreased. These molecules provide the chemical biology tools to determine the effect of modulating S1P levels in vivo. We also focused our investigation on the tail region of the pharmacophore. From this study, SLM6031434 and SLM6041418 were discovered and both proved to be more potent and selective SphK2 inhibitors than SLR080811. SLM6031434 has a Ki of 370 nM and is 23-fold selective for SphK2. SLM6041418 has a Ki of 430 nM and is 24-fold selective for SphK2. Consistent with our previous observations, in vitro studies showed a decrease in S1P levels when inhibitor was introduced. Similarly, in vivo studies resulted in an increase of S1P levels in the blood. These compounds are positioned towards animal models of disease. / Master of Science
40

Characterization of Influenza:Streptococcus pneumoniae synergistic disease and potential for disease alleviation via sphingolipid therapy

Gasser, Amanda Lynn 06 September 2013 (has links)
Influenza A virus (IAV) is generally associated with the seasonal malady that causes brief respiratory illness during the winter months, known simply as "the flu." Most otherwise healthy individuals will suffer from mild fever, congestion, headaches and myalgia that are resolved within 5-7 days of onset. However, there are nearly 500,000 influenza-related deaths that occur world-wide every year. Many of these casualties and patients hospitalized with influenza also test positive for bacterial pneumonia, the most common agent being Streptococcus pneumoniae. Although all individuals are subject to this viral:bacterial synergistic disease, the young, elderly, and immunocompromised are the most susceptible. Previous studies have shown that viral infection creates a prolonged hyper-responsive pro-inflammatory state in the lungs, which increases susceptibility to secondary bacterial infection. Lethality is due to detrimental pulmonary damage from a dysregulated host inflammatory response, known as the "cytokine storm." However, the nature of dual infection has not been well-studied in the elderly demographic. Therefore, we aim to better define this disease synergy in an aged mouse model and explore potential therapeutic alternatives that could be beneficial for the aged and other vulnerable populations. Sphingolipid modulation has emerged as a potential target to ameliorate the excessive inflammation (cytokine storm) elicited by highly pathogenic influenza. There is particular emphasis on sphingosine 1-phosphate (S1P) signaling, as well as control of intracellular S1P levels via sphingosine kinases (SK). Sphingolipids are involved in a multitude of cellular processes, and are tightly regulated by their metabolizing enzymes. We hypothesize that manipulation of sphingolipid signaling and alteration of the internal sphingolipid milieu will diminish the inflammatory response elicited by IAV infection. Using fluorescence-activated cell sorting (FACS), real-time PCR and cytometric bead array (CBA) analysis, we evaluated the immunomodulatory effects of systemic sphingosine analog treatment within the lung microenvironment under homeostatic and influenza-infected conditions. FTY720 treatment caused transient, but significant lymphopenia, influx of neutrophils and efflux of macrophages in the lungs, which was enhanced during a mild influenza infectionGene expression in the lungs was generally unaltered, but protein levels showed increases in specific influenza-induced cytokines, suggesting these treatments may have post-transcriptional effects on cytokine expression. To evaluate sphingolipid modulation in specific pulmonary cell types, we next observed the effects of these compounds and sphingosine kinase (SK) inhibitors in epithelial and alveolar macrophage-like cell lines. SK inhibitors and Enigmol demonstrated anti-viral effects in A549 cells, decreasing viral loads by up to 1.5 logs. Real-time PCR and CBA analysis further demonstrated that these effects were associated with alterations in key cytokine expression, including CCL2, CCL5, CXCL10, IL-6, and IL-8. Collectively, these findings indicate that therapeutic sphingolipid modulation has the potential for creating a protective microenvironment in the lungs that could alleviate or even prevent viral:bacterial synergistic disease. / Master of Science

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