Synthesis and biological evaluation of substituted phosphate triester alkyl lyso phospholipids (ALPs) as novel potential anti‐neoplastic agents

McGuigan, Christopher; Wang, Yikang; Riley, Patrick A.

doi:10.1016/0014-5793(95)00959-d

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…Cytotoxicity was determined using the MTT assay (Marks et al 1992) or by thymidine incorporation, compounds (14-27) as previously reported (McGuigan et al 1994). For the MTT assay, compounds were dissolved into 11 mM stock solutions in ethanol or culture medium depending on solubility.…”

Section: Cytotoxicity Assay Protocolmentioning

confidence: 99%

Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress

Dymond

Attard

Postle

2008

J. R. Soc. Interface.

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The alkyllysophospholipid (ALP) analogues Mitelfosine and Edelfosine are anticancer drugs whose mode of action is still the subject of debate. It is agreed that the primary interaction of these compounds is with cellular membranes. Furthermore, the membrane-associated protein CTP: phosphocholine cytidylyltransferase (CCT) has been proposed as the critical target. We present the evaluation of our hypothesis that ALP analogues disrupt membrane curvature elastic stress and inhibit membrane-associated protein activity (e.g. CCT), ultimately resulting in apoptosis. This hypothesis was tested by evaluating structure -activity relationships of ALPs from the literature. In addition we characterized the lipid typology, cytotoxicity and critical micelle concentration of novel ALP analogues that we synthesized. Overall we find the literature data and our experimental data provide excellent support for the hypothesis, which predicts that the most potent ALP analogues will be type I lipids.

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Section: Cytotoxicity Assay Protocolmentioning

confidence: 99%

Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress

Dymond

Attard

Postle

2008

J. R. Soc. Interface.

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“…The precedent figures illustrated the suppression of the phosphate moiety present in edelfosine thus producing cationic ether lipids. Another structural modification consisted in removing the cationic moiety and to substitute the phosphate function in order to isolate non-ionic ether lipids as reported by McGuigan et al in 1995 [ 188 ]. These non-ionic ether lipids were prepared by using 56.1 as starting material.…”

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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“…Drugs with these properties should be broad-spectrum antivirals, with low cytotoxicity and with reduced ability to select for resistance. Only one class of chemically synthesized compounds has been reported thus far to behave as a lipid-targeted membrane fusion inhibitor (15)(16)(17). However, the molecular mechanism underlying their antiviral activity is controversial (18).…”

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confidence: 99%

Surfactin Inhibits Membrane Fusion during Invasion of Epithelial Cells by Enveloped Viruses

Yuan

Zhang

Wang

et al. 2018

J Virol

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Because membrane fusion is a crucial step in the process by which enveloped viruses invade host cells, membrane fusion inhibitors can be effective drugs against enveloped viruses. We found that surfactin from can suppress the proliferation of porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV) in epithelial cells at a relatively low concentration range (15 to 50 μg/ml), without cytotoxicity or viral membrane disruption. Membrane fusion inhibition experiments demonstrate that surfactin treatment significantly reduces the rate at which the virus fuses to the cell membrane. Thermodynamic experiments show that the incorporation of small amounts of surfactin hinders the formation of negative curvature by lamellar-phase lipids, suggesting that surfactin acts a membrane fusion inhibitor. A fluorescent lipopeptide similar to surfactin was synthesized, and its ability to insert into the viral membrane was confirmed by spectroscopy. experiments have shown that oral administration of surfactin to piglets protects against PEDV infection. In conclusion, our study indicates that surfactin is a membrane fusion inhibitor with activity against enveloped viruses. As the first reported naturally occurring wedge lipid membrane fusion inhibitor, surfactin is likely to be a prototype for the development of a broad range of novel antiviral drugs. Membrane fusion inhibitors are a rapidly emerging class of antiviral drugs that inhibit the infection process of enveloped viruses. They can be classified, on the basis of the viral components targeted, as fusion protein targeting or membrane lipid targeting. Lipid-targeting membrane fusion inhibitors have a broader antiviral spectrum and are less likely to select for drug-resistant mutations. Here we show that surfactin is a membrane fusion inhibitor and has a strong antiviral effect. The insertion of surfactin into the viral envelope lipids reduces the probability of viral fusion. We also demonstrate that oral administration of surfactin protects piglets from PEDV infection. Surfactin is the first naturally occurring wedge lipid membrane fusion inhibitor that has been identified and may be effective against many viruses beyond the scope of this study. Understanding its mechanism of action provides a foundation for the development of novel antiviral agents.

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Synthesis and biological evaluation of substituted phosphate triester alkyl lyso phospholipids (ALPs) as novel potential anti‐neoplastic agents

Cited by 5 publications

References 11 publications

Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress

Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress

Synthesis of ether lipids: natural compounds and analogues

Surfactin Inhibits Membrane Fusion during Invasion of Epithelial Cells by Enveloped Viruses

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