Synthesis of <scp>D</scp>‐<i>Erythro</i>‐ and <scp>D</scp>‐<i>Threo</i>‐Sphingosine Derivatives From <scp>L</scp>‐Serine

Herold, Peter

doi:10.1002/hlca.19880710208

Cited by 224 publications

(100 citation statements)

References 33 publications

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“…Considering that our product was a Cram-selective isomer, we tried to add anhydrous ZnBr 2 or CuI to the aldol reaction to reach anti-Cram selectivity to get 3S-isomer. 11 However, this attempt failed to obtain any coupling products. At this moment we planned to continue the synthesis by reverting the configuration of the 3-OH of 3b.…”

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confidence: 95%

Total Synthesis of Kaitocephalin, the First Naturally Occurring AMPA/KA Receptor Antagonist

and

Yang

2001

J. Am. Chem. Soc.

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Excitatory neuronal transmission within the central nervous system (CNS) is mediated predominantly by L-glutamate, which plays a role of utmost importance in many physiological processes such as neural plasticity, memory, and learning. 1 However, excessive of L-glutamate release can result in neuronal cell death, a phenomenon that has been termed excitotoxcity. 2 It is now commonly accepted that excitotoxic cell death substantially contributes to the pathophysiology of both acute and chronic neurodegenerative disorders in the CNS. These disorders include epilepsy, focal and global ischaemia, stroke, pain, and neurodegenerative diseases. 3 These observations have stimulated considerable research efforts on the development of selective and potent antagonists for glutamate receptors, particularly compounds acting at the N-methyl-D-aspartate (NMDA), R-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainic acid (KA) receptor subtypes. 4 Some AMPA/KA receptor antagonists have shown promising usage for treatment of epilepsy and cerebrovascular ischemia. 5 In 1997, kaitocephalin, the first natural AMPA/KA antagonist, was isolated from Eupenicillium shearii. In the models of chick primary telencephalic and rat hippocampal neurons, this compound showed protection from kainate toxicity at 500 µM with EC 50 values being 0.68 and 2.4 µM, respectively, and from AMPA/cyclothiazide (500 µM/50‚M) toxicity with EC 50 values 0.6 and 0.4 µM, respectively. Unlike the known AMPA/KA antagonists with a quinoxalinedione skeleton, kaitocephalin does not have any cytotoxic effect. 6 Thus, SAR studies on this compound may open a new avenue to the development of therapeutic tools for protection of excitotoxicity. However, before comprehensive SAR studies become a reality, an efficient route to kaitocephalin is required. Toward this goal we report here the first total synthesis of kaitocephalin.On the basis of the proposed stereochemistry of kaitocephalin, 7 we described a synthetic plan as shown in Scheme 1. The 2,5-disubstituted pyrrolidines A were envisioned to be ideal building blocks for synthesizing the target molecule because its 2-position could be lithiated and then coupled with (R)-Garner aldehyde to assemble the right-hand part of kaitocephalin, and its C-C double bond could be converted into the left-hand moiety through Sharpless asymmetric dihydroxylation. 8 The detailed studies were outlined in Scheme 2. Protection of the acid and amide groups of (S)-pyroglutamic acid under ordinary conditions followed by reduction with DIBAL-H provided 1a and 1b. 9 Treatment of 1 with allyltrimethylsilane and TiCl 4 in methylene chloride afforded cis-2 as the major product, together with some separable transisomer. 10 The aldol condensation reaction was obviously a key step for this synthesis and therefore tested under many conditions. Initially, lithiation of 2a with LDA at -78°C followed by trapping the resultant anion with (R)-Garner aldehyde gave the condensation products quantitatively. However, it was found that four ...

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confidence: 95%

Total Synthesis of Kaitocephalin, the First Naturally Occurring AMPA/KA Receptor Antagonist

and

Yang

2001

J. Am. Chem. Soc.

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“…Lysophosphatidylcholine (lyso-PC) and lyso-platelet-activating factor (lyso-PAF) were purchased from Avanti. Sphingosine 1-phosphate was from Biomol, Plymouth Meeting, PA. Sphingosine stereoisomers were obtained in stereoselective synthesis starting from L-or D-serine, respectively (17). Dihydrosphingosine stereoisomers were prepared by hydrogenation over Pd/C (palladium on activated charcoal) of an adequate sphingosines.…”

Section: Methodsmentioning

confidence: 99%

Sphingosylphosphocholine Reduces the Calcium Ion Requirement for Activating Tissue Transglutaminase

Lai¹,

Bielawska²,

Peoples³

et al. 1997

Journal of Biological Chemistry

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Tissue transglutaminase (tTG) catalyzes a Ca2؉ -dependent transglutaminase reaction resulting in the formation of ␥-glutamyl-⑀-lysine bonds and is activated during apoptosis to catalyze the formation of apoptotic body. We investigate whether lipids that are membrane components and involved in cell signaling could modify the Ca 2؉ -dependent activation of tTG. We found that sphingosylphosphocholine (lyso-SM) was the only lipid to activate transglutaminase at low Ca 2؉ concentrations. In the presence of lyso-SM (125 M), transglutaminase was detectable at 10 M Ca 2؉ , whereas in the absence of lyso-SM, similar activity was obtained at 160 M Ca 2؉. Furthermore, in the presence of lipid vesicles lyso-SM retained the ability to enhance the Ca 2؉ -dependent activation of tTG. Lyso-SM did not significantly change the K m for the glutamyl and primary amine substrates. However, the K act for Ca 2؉ was reduced from 300 M to 90 M. Structure-function studies of lyso-SM analogs indicate that phosphocholine group on C1, the free amino group at C2 and a C4 -C5 double bond are critical for the activation of transglutaminase activity. This is the first demonstration that a specific sphingolipid could enhance the activity of tTG and could play a role in vivo in activation of the tTG at physiologic Ca 2؉ levels.Tissue transglutaminase (tTG) 1 is a calcium-dependent enzyme that plays an important role in many different intracellular and extracellular processes ranging from apoptosis to extracellular matrix formation (1-3). Calcium ions are required for the enzyme to adopt the proper conformation to bind glutamine and lysine residues within proteins or peptides (1-3). The intracellular levels of calcium are much lower than the reported calcium levels required to obtain measurable transglutaminase (TGase) activity in vitro. This raises the question of whether there are intracellular cofactor(s) that can modify the sensitivity of tTG to Ca 2ϩ . The tTG first forms a calciumdependent thioester bond with select protein bound glutamines and releases ammonia (1-4). The thioester is a reactive enzyme-substrate intermediate that can then react rapidly with the primary amine group of either a lysine within a protein or a polyamine (1-4). The final reaction product contains an isopeptide bond that stabilizes inter-and intramolecular protein structure or generates a protein-polyamine conjugate that has unique biologic properties (1-4).The binding of calcium ions reduces the affinity of tTG for GTP (5). GTP binding to tTG causes a conformational change in the protein which leads to a reduction in TGase activity (1-3). Based upon the affinity of the tTG for both calcium ions and GTP as well as the intracellular concentrations of these cofactors, the majority of the tTG in vivo is predicted to remain latent (1, 2, 6).tTG is reported to associate with phospholipid bilayers in vitro (7,8) and with cell membranes (9, 10). The recent discovery that a portion of the intracellular tTG is associated with the cytoplasmic domain of the cell membrane a...

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“…Various sphingosine stereoisomers were synthesized and purified as described previously (17)(18)(19). D-erythro-sphingosine and L-erythrosphingosine were prepared, respectively, from tert-butoxycarbonyl-Lserine and tert-butoxycarbonyl-D-serine via coupling of the Garner aldehyde (17) with lithium pentadecyne in hexamethylphosphoramidetetrahydrofuran as described by Herold (18), followed by Birch reduction in lithium-ethylamine as described by Garner (19).…”

Section: Preparation Of Sphingosine Stereoisomersmentioning

confidence: 99%

“…D-erythro-sphingosine and L-erythrosphingosine were prepared, respectively, from tert-butoxycarbonyl-Lserine and tert-butoxycarbonyl-D-serine via coupling of the Garner aldehyde (17) with lithium pentadecyne in hexamethylphosphoramidetetrahydrofuran as described by Herold (18), followed by Birch reduction in lithium-ethylamine as described by Garner (19). D-and L-threo-isomers were prepared in a similar manner, with the exception that coupling reactions were performed with lithium pentadecyne in the presence of zinc bromide in diethyl ether (18). Stereoisomers were characterized as N-biphenyl-carboxamido derivatives of sphingosine by high performance liquid chromatography on the basis of elution from a chiral column in hexane/2-propanol (8:2, v/v).…”

Section: Preparation Of Sphingosine Stereoisomersmentioning

confidence: 99%

Induction of Apoptosis and Potentiation of Ceramide-mediated Cytotoxicity by Sphingoid Bases in Human Myeloid Leukemia Cells

Jarvis

Fornari

Traylor

et al. 1996

Journal of Biological Chemistry

126

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). The present findings document the intrinsic ability of sphingoid bases to induce apoptosis in HL-60 and U937 cells. Exposure to either sphingosine or sphinganine (0.001-10 M) for 6 h promoted apoptotic degradation of genomic DNA as indicated by (a) electrophoretic resolution of 50-kilobase pair DNA loop fragments and 0.2-1.2-kilobase pair DNA fragment ladders on agarose gels, and (b) spectrofluorophotometric determination of the formation and release of double-stranded fragments and corresponding loss of integrity of bulk DNA. DNA damage correlated directly with reduced cloning efficiency and was associated with the appearance of apoptotic cytoarchitectural traits. At sublethal concentrations ( 750 nM), however, sphingoid bases synergistically augmented the apoptotic capacity of ceramide (10 M), producing both a leftward shift in the ceramide concentration-response profile and a pronounced increase in the response to maximally effective levels of ceramide. Thus, sphingosine and sphinganine increased both the potency and efficacy of ceramide. The apoptotic capacity of bacterial sphingomyelinase (50 milliunits/ml) was similarly enhanced by either (a) acute co-exposure to highly selective pharmacological inhibitors of protein kinase C such as calphostin C and chelerythrine or (b) chronic pre-exposure to the nontumor-promoting protein kinase C activator bryostatin 1, which completely down-modulated total assayable protein kinase C activity. These findings demonstrate that inhibition of protein kinase C by physiological or pharmacological agents potentiates the lethal actions of ceramide in human leukemia cells, providing further support for the emerging concept of a cytoprotective function of the protein kinase C isoenzyme family in the regulation of leukemic cell survival.Recent investigation has examined the participation of sphingophospholipid-and glycerophospholipid-derived messengers in the regulation of leukemic cell survival. We (1, 2) and others (3) have demonstrated that increased intracellular availability of ceramide induces programmed cell death or apoptosis in the human myeloid leukemia cell lines HL-60 and U937. Ceramide interacts with at least two distinct intracellular target enzymes, ceramide-activated protein kinase (4 -6) and ceramide-activated protein phosphatase (7-9). A cytotoxic role for ceramide-activated protein phosphatase and ceramideactivated protein kinase in ceramide action has been inferred, although the relative contributions of these enzymes to the initiation of apoptosis is presently uncertain (10, 11). A contrasting cytoprotective function of diglyceride and, therefore, of one or more isoforms of protein kinase C (PKC) 1 is supported by several lines of evidence. Increased intracellular availability of diglyceride abrogates the initiation of apoptotic DNA damage by ceramide in both HL-60 and U937 cells (1, 2); this effect is mimicked by such diverse pharmacological PKC activators as the stage 1 tumor promoters phorbol dibutyrate (2) and phorbol myristate acetate (2, 3), the stag...

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Synthesis of D‐Erythro‐ and D‐Threo‐Sphingosine Derivatives From L‐Serine

Cited by 224 publications

References 33 publications

Total Synthesis of Kaitocephalin, the First Naturally Occurring AMPA/KA Receptor Antagonist

Total Synthesis of Kaitocephalin, the First Naturally Occurring AMPA/KA Receptor Antagonist

Sphingosylphosphocholine Reduces the Calcium Ion Requirement for Activating Tissue Transglutaminase

Induction of Apoptosis and Potentiation of Ceramide-mediated Cytotoxicity by Sphingoid Bases in Human Myeloid Leukemia Cells

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