Structure–Activity Relationships of Glucosamine‐Derived Glycerolipids: the Role of the Anomeric Linkage, the Cationic Charge and the Glycero Moiety on the Antitumor Activity

Abstract

The potent antitumor activity of 1-O-hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl)-sn-glycerol (1) was previously shown to arise through an apoptosis-independent pathway. Here, a systematic structure-activity study in which the effects of the anomeric linkage, the cationic charge and the glycero moiety on the antitumor activity is described. Eight analogues of 1 were synthesized, and their antitumor activity against breast (JIMT1 and BT549), pancreas (MiaPaCa2) and prostate (DU145, PC3) cancer was determined. 1-O-Hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-α-D-glucopyranosyl)-sn-glycerol (2) consistently displayed the most potent activity against all five cell lines with CC(50) values in the range of 6-10 μM. However, replacement of the O-glycosidic linkage by a thioglycosidic linkage or replacement of the amino group by an azide or guanidino group leads to a threefold or greater decrease in potency. The glycero moiety also contributes to the overall activity of 1 and 2 but its effects are of lesser importance. Investigation into the mode of action of this class of compounds revealed that, in agreement with previous findings, the cytotoxic effects arise through induction of large acid vacuoles.

Structure Activity Relationships of N-linked and Diglycosylated Glucosamine-Based Antitumor Glycerolipids

“…Compounds 6 and 7 were synthesized to study the effects of diglycosylation and stereochemistry of the glycerol moiety on the antitumor properties. Glycolipids 6 and 7 were prepared from known thioglycoside donor 24 [22] by glycosylation with commercially lipid alcohol 25 or racemic alcohol 26 using silver triflate as catalyst and N -iodosuccinimde as promoter to afford protected glycolipids 27 or 28 , respectively (Scheme 2). The acetate and phthalimido protective groups were removed using ethylenediamine:butanol mixture (1:1) at 90 °C for 3 h to provide compounds 6 and 7 , respectively.…”

“…The cytotoxicity of compounds 1 – 7 was evaluated against a number of epithelial cancer cell lines using the MTS assay [22]. The cells were derived from cancers of the breast (JIMT-1, BT-474, MDA-MB-231), pancreas (MiaPaCa2), and prostrate (DU145, PC3).…”

“…Effects of compounds 2 – 4 on the viability of epithelial cancer cell lines: breast (BT474, JIMT1), prostrate (DU 145), pancreas (MiaPaCa2). The results represent the means ± standard deviations of six independent determinations (compound 1 is not included in this chart because we have previously published the data [22]). …”

“…The cytotoxicity assay was carried out using a previously reported method [22]. Cell viability was determined with the cell Titre 96 AQueous One Solution (MTS assay, Promega, Madison, WI, USA.…”

Replacing d-Glucosamine with Its l-Enantiomer in Glycosylated Antitumor Ether Lipids (GAELs) Retains Cytotoxic Effects against Epithelial Cancer Cells and Cancer Stem Cells

“…Glycosylated antitumor ether lipids (GAELs) such as 1 are an emerging class of glycolipids with potent cytotoxicity against human epithelial cancer cell lines. − Unique features of GAELs include their apoptosis-independent mechanism of cell death, likely through methuosis, , and an ability to kill cancer stem cells (CSCs), a rare property not found in most clinical anticancer drugs. Increasing experimental data supports the notion that CSCs are responsible for tumor metastasis, relapse, and resistance to both radio- and chemotherapy .…”