Stereoselektive Synthese von langkettigen 1‐O‐(β‐D‐Maltosyl)‐3‐O‐alkyl‐sn‐glycerinen (Alkylglycerylether‐Lysoglycolipide)

Prinz, Harald; Six, Lambert; Rueβ, Klaus-Peter; Liefländer, Manfred

doi:10.1002/jlac.198519850202

Cited by 19 publications

(6 citation statements)

References 17 publications

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“…Their anticancer activities have been established and reported. 18 Despite these widely known cytostatic and cytotoxic 38 Moreover, with the initial assumption that all AELs possess similar mechanism of actions, it was only logical to pursue the most promising of this category (edelfosine, ALPs). The discovery that GAELs mediate cytotoxicity via a novel non-apoptotic mechanism, 34 injected new enthusiasm towards developing clinically relevant analogs.…”

Section: Glycosylated Antitumor Ether Lipidsmentioning

confidence: 99%

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Idowu

Samadder

Arthur

et al. 2016

Chemistry and Physics of Lipids

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The development of resistance to apoptotic pathways by cancer cells is one of the great impediments to the successful use of chemotherapeutic agents. The development of resistance may be attributed to the role of cancer stem cells in the progression of this disease. One approach to combat drug resistance involves the use of drug combinations that impact multiple targets simultaneously. Although this is believed to be better at controlling complex disease systems, it has often proven to be of limited benefits in terms of overall therapeutic outcomes in cancer treatment. Glycosylated antitumor ether lipids (GAELs) are an emerging class of novel anticancer molecules that is being investigated as potential anticancer drugs. Interest in this class of drug is based on their ability to kill cancer stem cells as well as their non-apoptotic mechanism of action. This provides new opportunities to manipulate cell death in a therapeutic context, especially the renewed ability to kill apoptosis-resistant cancer cells. We therefore hypothesized that hybrid molecules that combine apoptosis-dependent and apoptosis-independent mode of actions in a single molecule may lead to better therapeutic outcomes. We also posited that the amphiphilic nature of GAELs could be modulated and fine-tuned to give a more potent analog.This dissertation describes the antitumor activities of different analogs of GAELchlorambucil hybrids and different triamino analogs. In all, eleven GAEL analogs were synthesized. Their activities, as well as that of reference compounds, were assessed against breast (JIMT1, MDA-MB-231, BT474), pancreas (MiaPaCa2) and prostate (DU145, PC3) cancer cell lines using the MTS assay. Our results reveal that the hybrid concept is a potential viable avenue to pursue as a therapeutic option especially when the other domain is carefully selected (Chapter 3). Moreover, the evidently more potent triamino analog not only corroborate the plausibility of a hybrid drug, it also revealed an important detail about the amphiphilic-cytotoxic relationships of GAELs (Chapter 4). iv ACKNOWLEDGEMENTSMy heartfelt appreciation goes to my indefatigable supervisor, Dr. Frank Schweizer, for his unquantifiable support and understanding, and also for guiding my feet through the 'wilderness' of organic synthesis. His astuteness, inquisitiveness, resourcefulness and right amount of scientific skepticism have rightly shaped me in the pursuit of excellence. He is ever ready and willing to help whenever I run into troubled waters.Also to my co-supervisor, my committee member and our long-standing collaborator, Dr.Gilbert Arthur: his calmness, dexterity, and keen attention to details are unparalleled and 'contagious'. The invaluable contributions of Dr. Pranati Samadder to the success of this work are also deeply appreciated.Many thanks to members of my examining committee: Drs. Jorg Stetefeld, Rebecca Davis and Gilbert Arthur, for your patience, constructive feedbacks and quick response whenever I beckon on you. It was a delight having you all ...

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Section: Glycosylated Antitumor Ether Lipidsmentioning

confidence: 99%

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Idowu

Samadder

Arthur

et al. 2016

Chemistry and Physics of Lipids

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“…Solketal 1 is the common commercial precursor to prepare O -alkyl glycerol 4 since the free alcohol function can be deprotonated and then engaged in an alkylation reaction with a lipid alcohol activated with a mesyl functional group or directly with a halogenoalkyl. Prinz et al [ 37 ] used KOH to deprotonate solketal in benzene and then myristoylmethanesulfonate (C14:0) or palmitoylmethanesulfonate (C16:0) was added. After alcohol deprotection with HCl in methanol, the alkylglycerol 4a (C14:0) and 4b (C16:0) were isolated in 77–85% yield (two steps).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Alkyl-Glycerolipids Standards for Gas Chromatography Analysis: Application for Chimera and Shark Liver Oils

et al. 2018

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Natural O-alkyl-glycerolipids, also known as alkyl-ether-lipids (AEL), feature a long fatty alkyl chain linked to the glycerol unit by an ether bond. AEL are ubiquitously found in different tissues but, are abundant in shark liver oil, breast milk, red blood cells, blood plasma, and bone marrow. Only a few AEL are commercially available, while many others with saturated or mono-unsaturated alkyl chains of variable length are not available. These compounds are, however, necessary as standards for analytical methods. Here, we investigated different reported procedures and we adapted some of them to prepare a series of 1-O-alkyl-glycerols featuring mainly saturated alkyl chains of various lengths (14:0, 16:0, 17:0, 19:0, 20:0, 22:0) and two monounsaturated chains (16:1, 18:1). All of these standards were fully characterized by NMR and GC-MS. Finally, we used these standards to identify the AEL subtypes in shark and chimera liver oils. The distribution of the identified AEL were: 14:0 (20–24%), 16:0 (42–54%) and 18:1 (6–16%) and, to a lesser extent, (0.2–2%) for each of the following: 16:1, 17:0, 18:0, and 20:0. These standards open the possibilities to identify AEL subtypes in tumours and compare their composition to those of non-tumour tissues.

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“…The synthesis of glycerol-based lipids functionalized with a saccharide moiety have interested many chemists from the beginning of the 70’s [ 199 ]. In the 80’s, the synthesis of glycerol monoether [ 200 ] or diether with two lipid chains [ 201 – 202 ] and with different saccharide moieties (e.g., glucopyranosyl [ 203 ], 2-desoxy-2-fluoromannopyranosyl [ 204 ]) was reported. One of the first studies that reports the synthesis of glycerol diether including a methoxy group in position 3 of the glycerol was published by N. Weber and H. Benning in 1986 [ 205 ].…”

Section: Reviewmentioning

confidence: 99%

Synthesis of ether lipids: natural compounds and analogues

Gomes,

Bauduin,

Le Roux

et al. 2023

Beilstein J. Org. Chem.

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Ether lipids are compounds present in many living organisms including humans that feature an ether bond linkage at the sn-1 position of the glycerol. This class of lipids features singular structural roles and biological functions. Alkyl ether lipids and alkenyl ether lipids (also identified as plasmalogens) correspond to the two sub-classes of naturally occurring ether lipids. In 1979 the discovery of the structure of the platelet-activating factor (PAF) that belongs to the alkyl ether class of lipids increased the interest in these bioactive lipids and further promoted the synthesis of non-natural ether lipids that was initiated in the late 60’s with the development of edelfosine (an anticancer drug). More recently, ohmline, a glyco glycero ether lipid that modulates selectively SK3 ion channels and reduces in vivo the occurrence of bone metastases, and other glyco glycero ether also identified as GAEL (glycosylated antitumor ether lipids) that exhibit promising anticancer properties renew the interest in this class of compounds. Indeed, ether lipid represent a new and promising class of compounds featuring the capacity to modulate selectively the activity of some membrane proteins or, for other compounds, feature antiproliferative properties via an original mechanism of action. The increasing interest in studying ether lipids for fundamental and applied researches invited to review the methodologies developed to prepare ether lipids. In this review we focus on the synthetic method used for the preparation of alkyl ether lipids either naturally occurring ether lipids (e.g., PAF) or synthetic derivatives that were developed to study their biological properties. The synthesis of neutral or charged ether lipids are reported with the aim to assemble in this review the most frequently used methodologies to prepare this specific class of compounds.

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Stereoselektive Synthese von langkettigen 1‐O‐(β‐D‐Maltosyl)‐3‐O‐alkyl‐sn‐glycerinen (Alkylglycerylether‐Lysoglycolipide)

Cited by 19 publications

References 17 publications

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Synthesis of Alkyl-Glycerolipids Standards for Gas Chromatography Analysis: Application for Chimera and Shark Liver Oils

Synthesis of ether lipids: natural compounds and analogues

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