Synthesis and Growth Inhibitory Properties of Glycosides of 1-O-Hexadecyl-2-O-methyl-sn-glycerol, Analogs of the Antitumor Ether Lipid ET-18-OCH3 (Edelfosine)

Mariño-Albernas, Jose R.; Bittman, Robert; Peters, A.; Mayhew, E.

doi:10.1021/jm960164j

Cited by 35 publications

(22 citation statements)

References 22 publications

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“…They were found to be potent inhibitors of cell migration and might be relevant in controlling cancer metastasis. 48,49 Other amino-sugar-derived GAELs such as mannosamine and galactosamine have also shown modest activity comparable to glucosamine-derived analogs. Worthy of mention is the fact that α-galactosamine-derived analogs displayed greater activity than α-GDG 1, whereas its β-counterpart showed between 4-to 5-fold loss of activity.…”

Section: Structure-activity Relationships (Sar)mentioning

confidence: 99%

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Idowu

Samadder

Arthur

et al. 2016

Chemistry and Physics of Lipids

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The development of resistance to apoptotic pathways by cancer cells is one of the great impediments to the successful use of chemotherapeutic agents. The development of resistance may be attributed to the role of cancer stem cells in the progression of this disease. One approach to combat drug resistance involves the use of drug combinations that impact multiple targets simultaneously. Although this is believed to be better at controlling complex disease systems, it has often proven to be of limited benefits in terms of overall therapeutic outcomes in cancer treatment. Glycosylated antitumor ether lipids (GAELs) are an emerging class of novel anticancer molecules that is being investigated as potential anticancer drugs. Interest in this class of drug is based on their ability to kill cancer stem cells as well as their non-apoptotic mechanism of action. This provides new opportunities to manipulate cell death in a therapeutic context, especially the renewed ability to kill apoptosis-resistant cancer cells. We therefore hypothesized that hybrid molecules that combine apoptosis-dependent and apoptosis-independent mode of actions in a single molecule may lead to better therapeutic outcomes. We also posited that the amphiphilic nature of GAELs could be modulated and fine-tuned to give a more potent analog.This dissertation describes the antitumor activities of different analogs of GAELchlorambucil hybrids and different triamino analogs. In all, eleven GAEL analogs were synthesized. Their activities, as well as that of reference compounds, were assessed against breast (JIMT1, MDA-MB-231, BT474), pancreas (MiaPaCa2) and prostate (DU145, PC3) cancer cell lines using the MTS assay. Our results reveal that the hybrid concept is a potential viable avenue to pursue as a therapeutic option especially when the other domain is carefully selected (Chapter 3). Moreover, the evidently more potent triamino analog not only corroborate the plausibility of a hybrid drug, it also revealed an important detail about the amphiphilic-cytotoxic relationships of GAELs (Chapter 4). iv ACKNOWLEDGEMENTSMy heartfelt appreciation goes to my indefatigable supervisor, Dr. Frank Schweizer, for his unquantifiable support and understanding, and also for guiding my feet through the 'wilderness' of organic synthesis. His astuteness, inquisitiveness, resourcefulness and right amount of scientific skepticism have rightly shaped me in the pursuit of excellence. He is ever ready and willing to help whenever I run into troubled waters.Also to my co-supervisor, my committee member and our long-standing collaborator, Dr.Gilbert Arthur: his calmness, dexterity, and keen attention to details are unparalleled and 'contagious'. The invaluable contributions of Dr. Pranati Samadder to the success of this work are also deeply appreciated.Many thanks to members of my examining committee: Drs. Jorg Stetefeld, Rebecca Davis and Gilbert Arthur, for your patience, constructive feedbacks and quick response whenever I beckon on you. It was a delight having you all ...

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Section: Structure-activity Relationships (Sar)mentioning

confidence: 99%

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Idowu

Samadder

Arthur

et al. 2016

Chemistry and Physics of Lipids

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“…The group of Bittman replaced the phosphocholine head group by a carbohydrate moiety. This replacement resulted in improved efficacy in comparison to non‐glycosidated, phosphocholine‐containing compounds (Marino‐albernas et al. , 1996; Samadder et al.…”

Section: Concept Of Glycosidated Phospholipid Analoguesmentioning

confidence: 99%

Glycosidated phospholipids: uncoupling of signalling pathways at the plasma membrane

Danker

Reutter

Semini

2010

British J Pharmacology

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Cell expansion and metastasis are considered hallmarks of tumour progression. Therefore, efforts have been made to develop novel anti-cancer drugs that inhibit both the proliferation and the motility of tumour cells. Synthetic alkylphospholipids, compounds with aliphatic side chains that are ether linked to a glycerol backbone, are structurally derived from plateletactivating factor and represent a new class of drugs with anti-proliferative properties in tumour cells. These compounds do not interfere with the DNA or mitotic spindle apparatus of the cell. Instead, they are incorporated into cell membranes, where they accumulate and interfere with lipid metabolism and lipid-dependent signalling pathways. Recently, it has been shown that the most commonly studied alkylphospholipids inhibit proliferation by inducing apoptosis in malignant cells while leaving normal cells unaffected. This review focuses on a novel group of synthetic alkylphospholipids, the glycosidated phospholipids, which contain carbohydrates or carbohydrate-related molecules at the sn-2 position of the glycerol backbone. Members of this subfamily also exhibit anti-proliferative capacity and modulate the cell adhesion, differentiation, and migration of tumour cells. Among this group, Ino-C2-PAF shows the highest efficacy and low cytotoxicity. Apart from its anti-proliferative effect, Ino-C2-PAF strongly reduces cell motility via its inhibitory effect on the phosphorylation of the cytosolic tyrosine kinases FAK and Src. Signalling pathways under the control of the FAK/Src complex are normally required for both migration and proliferation and play a prominent role in tumour progression. We intend to highlight the potential of glycosidated phospholipids, especially Ino-C2-PAF, as a promising new group of drugs for the treatment of hyperproliferative and migration-based skin diseases.

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“…Replacement of the sn-3 phosphocholine residue by different monosaccharides results in more effective analogues, compared to non-glycosidated, phosphocholine-containing compounds [19,20]. Replacement of the sn-3 phosphocholine residue by different monosaccharides results in more effective analogues, compared to non-glycosidated, phosphocholine-containing compounds [19,20].…”

Section: Structures Of Synthetic Glycosidated Phospholipid Analoguesmentioning

confidence: 99%

Modified and Modifying Sugars as a New Tool for the Development of Therapeutic Agents – Glycosidated Phospholipids as a New Type of Antiproliferative Agents

Danker¹,

Fischer²,

Reutter³

2003

Carbohydrate‐Based Drug Discovery

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Synthesis and Growth Inhibitory Properties of Glycosides of 1-O-Hexadecyl-2-O-methyl-sn-glycerol, Analogs of the Antitumor Ether Lipid ET-18-OCH₃ (Edelfosine)

Cited by 35 publications

References 22 publications

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Glycosidated phospholipids: uncoupling of signalling pathways at the plasma membrane

Modified and Modifying Sugars as a New Tool for the Development of Therapeutic Agents – Glycosidated Phospholipids as a New Type of Antiproliferative Agents

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