Antitumor ether lipids (AEL) are structural analogs of PAF, but lack the readily hydrolyzable ester substituent at the sn-2 position of glycerol moiety (Fig. 11.1). They contain a long carbon chain at the sn-1 and a short chain at the sn-2 position. At the sn-3 position, phosphocholine is the head group. Examples of common AEL are Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, Et-18-OCH3); Ilmofosine; Miltefosine (hexadecylphosphocholine, HePC); ilmofosine (BM 41.440, 1-hexadecylthio-2-methoxymethyl-rac-glycero- 3-phosphocholine); and SR1 62-834 ( (+-)-2-(Hydroxy[tetrahydro-2-(octadecyloxy) methylfuran-2-yl] methoxyl phosphinyloxy)-N,N,N-trimethylethaniminium hydroxide). HePC lacks the glycerol backbone. Alkyl-phosphocholine and alkyl-glycerophosphocholine derivatives as well as aza-substituted alkylglycerophosphocholines have also been synthesized. These derivatives include 1-methoxy-2-N,N-methyl-octadecylamino-propyloxyphosphorylcholine (BN 52205), 1-methoxy-3-N,N-methyl-octadecylamino-propyloxyphosphorylcholine (BN 52207), 1-N,N-methyl-octadecylamino-2-methoxy-propyloxyphosphorylcholine (BN 52211) (Fig. 11.2). Besides the above-mentioned anticancer compounds, glycosidated phospholipids such as 2-glucophosphatidylcholine (1-stearoyl-2-O-α-dglucopyranoside-sn-glycero-3-phosphocholine) and Glc-PAF (1-O-octadecyl- 2-O-α-d-glucopyranosyl-sn-2-glycero-3-phosphatidylcholine) and other alkylphosphocholines have been synthesized (Fig. 11.3). All these compounds inhibit cell proliferation in HaCaT cells (Fischer et al., 2006). The substitution of myo-inositol, in place of α-d-glucose, in the sn-2 position of the glycerol moiety leads to two diastereomeric 1-O-octadecyl-2-O-(2-(myo-inositolyl)-ethyl)-snglycero- 3-(R/S)-phosphatidylcholines (Ino-C2-PAF). The inositol-containing PAF enhances the antiproliferative capacity (IC50 = 1.8 μM) and reduces the cytotoxicity relative to Glc-PAF (LC50 = 15μM). AEL are taken up in the tumor cell more rapidly than normal cells. Several mechanisms have been proposed for AEL uptake. They include passive diffusion (Kelley et al 1993), internalization through endocytosis (Bazill and Dexter, 1990), and active uptake through a carrier (Hanson et al., 2003; Perez-Victoria et al., 2003; Ménez et al., 2007).
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(2008). Biochemical Effects of Nonphysiological Antitumor Ether Lipids. In: Metabolism and Functions of Bioactive Ether Lipids in the Brain. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77401-5_11
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