An Efficient New Route to Plasmenyl-type Lipids:  Synthesis and Cytotoxicity of a Plasmenylcholine Analogue of the Antitumor Ether Lipid ET-18-OMe

Shin, Junhwa; Qualls, Marquita M.; Boomer, Jeremy A.; Robarge, Jason; Thompson, David H.

doi:10.1021/ja005522t

Cited by 17 publications

(19 citation statements)

References 23 publications

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“…We adopted TBS protection, which predominantly provides the 1,3-protected product through a steric effect instead of the conventional benzylidene acetal protection, in which 1,2-protection is preferred . The subsequent steps proceeded according to literature reports. , …”

Section: Resultsmentioning

confidence: 99%

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Methoxy-Functionalized Glycerol-Based Aliphatic Polycarbonate: Organocatalytic Synthesis, Blood Compatibility, and Hydrolytic Property

Montagna

Takahashi

Tsai

et al. 2021

ACS Biomater. Sci. Eng.

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Polymers that are biocompatible and degradable are desired for tissue engineering approaches in the treatment of vascular diseases, especially for those involving small-diameter blood vessels. Herein, we report the compatibility of a newly developed glycerol-based aliphatic polycarbonate possessing simple methoxy side groups, named poly(5-methoxy-1,3-dioxan-2one) (PMDO), with blood cells and plasma proteins as well as its susceptibility to hydrolysis. As a consequence of the organocatalytic ringopening polymerization (ROP) of a methoxy-functionalized cyclic carbonate derived from glycerol, PMDO with a sufficiently high molecular weight (M n 14 kg/mol) and a narrow distribution (D̵ M 1.12) was obtained for evaluation as a bulk biomaterial. This study demonstrates for the first time the organocatalytic ROP of a glycerol-based cyclic carbonate in a controlled manner. Compared with the clinically applied aliphatic polycarbonate poly(trimethylene carbonate) (PTMC), PMDO inhibits platelet adhesion by 33% and denaturation of fibrinogen by 23%. Although the wettability of PMDO based on water contact angle was almost comparable to those of PTMC and poly(ethylene terephthalate), the reason for the inhibited platelet adhesion and protein denaturation appeared to be related to the presence of specific hydrated water formed in the hydrated polymer. The improved hydration of PMDO also enhanced the susceptibility to hydrolysis, with PMDO demonstrating a slightly higher hydrolytic property than PTMC. This simple glycerol-based aliphatic polycarbonate has the following benefits: bio-based characteristics of glycerol and improved blood compatibility and hydrolytic biodegradability stemming from moderate hydration of the methoxy side groups.

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Section: Resultsmentioning

confidence: 99%

“…29 The subsequent steps proceeded according to literature reports. 15,30 ROP of six-membered cyclic carbonates derived from glycerol was often performed in bulk using Sn(Oct) 2 with heating over 100 °C. 16,17,19,31,32 In addition, the use of enzymes or some organic catalysts was reported.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Methoxy-Functionalized Glycerol-Based Aliphatic Polycarbonate: Organocatalytic Synthesis, Blood Compatibility, and Hydrolytic Property

Montagna

Takahashi

Tsai

et al. 2021

ACS Biomater. Sci. Eng.

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“…Several studies combining the more recent ether lipids derivatives with diverse antineoplastic agents provide clinically significant benefits [ 99 ]. Shin et al [ 102 ] described the synthetic pathway applied to the synthesis of 1-O-1′- (Z) -hexadecenyl-2-O-methyl-rac-glycero-3-phosphocholine, the Z-vinyl ether analogue of ET-18- OMe, which shows significant antitumor activity in pancreatic tumor cells. Also, Bittman et al [ 103 ] reported the incorporation of a cis - O -vinyl linkage into the sn -1 position of glycerol of plasmalogens to synthesize a new antitumor ether lipid analogue of ET-18–OCH 3 .…”

Section: Anti-tumor Properties Of Synthetic Plasmalogens and Analoguementioning

confidence: 99%

Plasmalogen lipids: functional mechanism and their involvement in gastrointestinal cancer

et al. 2018

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The plasmalogens are a class of glycerophospholipids which contain a vinyl-ether and an ester bond at the sn-1 and sn-2 positions, respectively, in the glycerol backbone. They constitute 10 mol% of the total mass of phospholipids in humans, mainly as membrane structure components. Plasmalogens are important for the organization and stability of lipid raft microdomains and cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Although the clinical significance of plasmalogens is linked to peroxisomal disorders, the pathophysiological roles and their possible metabolic pathways are not fully understood since they present unique structural attributes for the different tissue types. Studies suggest that changes in plasmalogen metabolism may contribute to the development of various types of cancer. Here, we review the molecular characteristics of plasmalogens in order to significantly increase our understanding of the plasmalogen molecule and its involvement in gastrointestinal cancers as well as other types of cancers.Electronic supplementary materialThe online version of this article (10.1186/s12944-018-0685-9) contains supplementary material, which is available to authorized users.

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“…Synthetic antitumor lipids (ATLs) can be classified into two major categories (Fig. (1) [13][14][15][16][17]; b) phosphonate-derived ether lipids [18,19]; c) plasmenyl analogues of ET-18-OCH 3 [20,21]; d) new analogues of HPC, such as erucylphosphocholine [22,23] and perifosine [24,25]; e) phosphocholine-containing analogues of sphingomyelin [26]; f) alkylphosphonophosphate analogues of 1-β-D-arabinofuranosylcytosine (ara-C), such as cytoros [27]. The present review focuses on the current knowledge and new insights about the uptake, metabolism, mechanism of action and biomedical activities of ET-18-OCH 3 , as the prototype of AEPs, that can be extended to other ATLs.…”

Section: Two Major Types Of Antitumor Lipidsmentioning

confidence: 99%

“…of the antitumor ether lipid ET-18-OCH 3 , incorporating a cis-O-vinyl linkage into the sn-1 position of the glycerol backbone, have been synthesized very recently and show an antiproliferative effect in tumor cell lines in vitro[20,21].…”

mentioning

confidence: 99%

Biological Activities, Mechanisms of Action and Biomedical Prospect of the Antitumor Ether Phospholipid ET-18-OCH3 (Edelfosine), A Proapoptotic Agent in Tumor Cells

Gajate¹,

Mollinedo

2002

CDM

153

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The antitumor ether lipid ET-18-OCH(3) (edelfosine) is the prototype of a new class of antineoplastic agents, synthetic analogues of lysophosphatidylcholine, that shows a high metabolic stability, does not interact with DNA and shows a selective apoptotic response in tumor cells, sparing normal cells. Unlike currently used antitumor drugs, ET-18-OCH(3) does not act directly on the formation and function of the replication machinery, and thereby its effects are independent of the proliferative state of target cells. Because of its capacity to modulate cellular regulatory and signaling events, including those failing in cancer cells, like defective apoptosis, ET-18-OCH(3), beyond its putative clinical importance, is an interesting model compound for the development of more selective drugs for cancer therapy. Although ET-18-OCH(3) enhances host defense mechanisms against tumors, its major antitumor action lies in a direct effect on cancer cells, inhibiting phosphatidylcholine biosynthesis and inducing apoptosis in tumor cells. Recent progress has allowed unraveling the molecular mechanism underlying the apoptotic action of ET-18-OCH(3), leading to the notion that ET-18-OCH(3) is selectively incorporated into tumor cells and induces cell death by intracellular activation of the cell death receptor Fas/CD95. This intracellular Fas/CD95 activation is a novel mechanism of action for an antitumor drug and represents a new way to target tumor cells in cancer chemotherapy that can be of interest as a new framework in designing novel antitumor drugs. ET-18-OCH(3) and some analogues are pleiotropic agents that affect additional biomedical important diseases, including parasitic and autoimmune diseases, suggesting new therapeutic indications for these compounds.

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An Efficient New Route to Plasmenyl-type Lipids: Synthesis and Cytotoxicity of a Plasmenylcholine Analogue of the Antitumor Ether Lipid ET-18-OMe

Cited by 17 publications

References 23 publications

Methoxy-Functionalized Glycerol-Based Aliphatic Polycarbonate: Organocatalytic Synthesis, Blood Compatibility, and Hydrolytic Property

Methoxy-Functionalized Glycerol-Based Aliphatic Polycarbonate: Organocatalytic Synthesis, Blood Compatibility, and Hydrolytic Property

Plasmalogen lipids: functional mechanism and their involvement in gastrointestinal cancer

Biological Activities, Mechanisms of Action and Biomedical Prospect of the Antitumor Ether Phospholipid ET-18-OCH3 (Edelfosine), A Proapoptotic Agent in Tumor Cells

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