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Molecules 2013, 18(12), 15288-15304; doi:10.3390/molecules181215288

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

1
Department of Chemistry, University of Manitoba, 144 Dysart Rd, Winnipeg, MB R3T 2N2, Canada
2
Department of Biochemistry and Medical Genetics, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada
*
Author to whom correspondence should be addressed.
Received: 15 November 2013 / Revised: 3 December 2013 / Accepted: 4 December 2013 / Published: 10 December 2013
(This article belongs to the Section Medicinal Chemistry)
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Abstract

1-O-Hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl)-sn-glycerol (1) was previously reported to show potent in vitro antitumor activity on a range of cancer cell lines derived from breast, pancreas and prostate cancer. This compound was not toxic to mice and was inactive against breast tumor xenografts in mice. This inactivity was attributed to hydrolysis of the glycosidic linkage by glycosidases. Here three N-linked (glycosylamide) analogs 24, one triazole-linked analog 5 of 1 as well as two diglycosylated analogs 6 and 7 with different stereochemistry at the C2-position of the glycerol moiety were synthesized and their antitumor activity against breast (JIMT-1, BT-474, MDA-MB-231), pancreas (MiaPaCa2) and prostrate (DU145, PC3) cancer cell lines was determined. The diglycosylated analogs 1-O-hexadecyl-2(R)-, 3-O-di-(2'-amino-2'-deoxy-β-D-glucopyranosyl)-sn-glycerol (7) and the 1:1 diastereomeric mixture of 1-O-hexadecyl-2(R/S), 3-O-di-(2'-amino-2'-deoxy-β-D-glucopyranosyl)-sn-glycerol (6) showed the most potent cytotoxic activity at CC50 values of 17.5 µM against PC3 cell lines. The replacement of the O-glycosidic linkage by a glycosylamide or a glycosyltriazole linkage showed little or no activity at highest concentration tested (30 µM), whereas the replacement of the glycerol moiety by triazole resulted in CC50 values in the range of 20 to 30 µM. In conclusion, the replacement of the O-glycosidic linkage by an N-glycosidic linkage or triazole-linkage resulted in about a two to three fold loss in activity, whereas the replacement of the methoxy group on the glycerol backbone by a second glucosamine moiety did not improve the activity. The stereochemistry at the C2-position of the glycero backbone has minimal effect on the anticancer activities of these diglycosylated analogs.
Keywords: antitumor ether lipids; glycolipids; anticancer agents; carbohydrates antitumor ether lipids; glycolipids; anticancer agents; carbohydrates
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Ogunsina, M.; Pan, H.; Samadder, P.; Arthur, G.; Schweizer, F. Structure Activity Relationships of N-linked and Diglycosylated Glucosamine-Based Antitumor Glycerolipids. Molecules 2013, 18, 15288-15304.

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