Structural activity and mechanistic studies on glycosylated antitumor ether lipids (GAELs)
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Date
2016-08, 2013-10, 2013-03, 2015-04, 2015-12
Authors
Ogunsina, Makanjuola Ojo
Journal Title
Journal ISSN
Volume Title
Publisher
Medicinal Chemistry Communication
Molecules
MedChemMed
RSC Drug Discovery
Patent WO/2015/179983
Molecules
MedChemMed
RSC Drug Discovery
Patent WO/2015/179983
Abstract
A major impediment to successful treatment of cancer is the inability of clinically available drugs to kill cancer stems cells (CSCs), a subset of tumor cells that mediate progression, resistance and relapse of cancer. Glycosylated Antitumor Ether Lipids (GAELs), a class of amphiphilic antitumor agents such as 1-O-Hexadecyl-2-O-methyl-3-O-(2’-amino-2’-deoxy–β-Dglucopyranosyl)-sn-glycerol (GLN), represent a new class of anticancer agents that kill cancer cells by a non-apoptotic pathway, an attractive approach to overcome resistance to many pro-apoptotic anticancer agents. Previous studies show that GLN displayed potent cytotoxic effects against breast cancer stem cells, inhibited the formation of tumor spheres and caused the disintegration of preformed BT474 CSCs’ spheroids. A major challenge to clinical development of GAELs such as GLN is lack of activity in xenograft model. This has been associated to metabolic degradation in animal, a problem common to O-glycosides of D-Sugars. To take advantage of interesting pharmacological features of GAELs, we here explore structural features that are pivotal to activity for optimizing anticancer activity. Then, various strategies were employed to enhance metabolic stability. This thesis presents the outcome of structural activity studies on GLN and strategies used to overcome metabolic degradation in GAELs. Our result showed that unsubstituted amines, O-glycosidic linkage and glycerolipid are very crucial to activity. Metabolic stability can be achieved by using an L-enantiomer of the sugar without sacrificing potency. Mechanistic studies showed that the potent GAELs analogs discovered in this study kill cancer cells by non-apoptotic mode of action. Also, the GAELs enter the cells but do not lyse or disrupt the cell membrane. Moreover, the cytotoxicity of potent analogs of GAELs discovered is better than that of clinical anticancer drugs like cisplatin, chlorambucil and the experimental anti-CSCs agent salinomycin. These analogs are potential drug candidates for clinical development as new anticancer agents. Also, the use of L-sugar to resist metabolic degradation opens new opportunities for development of stable glyco-based drugs.
Description
Keywords
Cancer stem cells, L-sugar, Glycosylated antitumor ether lipids, cancer, anti-cancer stem cells' agents, glycoside
Citation
Ogunsina, Makanjuola, Pranati Samadder, Temilolu Idowu, Gilbert Arthur, and Frank Schweizer. 2016. “Design, Synthesis and Evaluation of Cytotoxic Properties of Bisamino Glucosylated Antitumor Ether Lipids against Cancer Cells and Cancer Stem Cells.” Med. Chem. Commun. The Royal Society of Chemistry. doi:10.1039/C6MD00328A.
Ogunsina, Makanjuola, Hangyi Pan, Pranati Samadder, Gilbert Arthur, and Frank Schweizer. 2013. “Structure Activity Relationships of N-Linked and Diglycosylated Glucosamine-Based Antitumor Glycerolipids.” Molecules (Basel, Switzerland) 18 (12). Multidisciplinary Digital Publishing Institute: 15288–304. doi:10.3390/molecules181215288.
Xu, Yaozu, Makanjuola Ogunsina, Pranati Samadder, Gilbert Arthur, and Frank Schweizer. 2013. “Structure-Activity Relationships of Glucosamine-Derived Glycerolipids: The Role of the Anomeric Linkage, the Cationic Charge and the Glycero Moiety on the Antitumor Activity.” ChemMedChem 8 (3): 511–20. doi:10.1002/cmdc.201200489.
Ogunsina, Makanjuola Pranati Samadder, Frank Schweizer, Gilbert Arthur, And Temilolu Idowu. 2015. “Di- and Tri-Cationic Glycosylated Antitumor Ether Lipids, L-Gucosylated GAELs and Rhamnose-Linked GAELs as Cytotoxic Agents against Epithelial Cancer Cells and Cancer Stem Cells.” https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015179983&recNum=161&docAn=CA2015050490&queryString=FP:(%22cancer%22) AND EN_ALL:nmr&maxRec=27681.
Arthur, Gilbert, Frank Schweizer, and Makanjuola Ogunsina. 2015. “Carbohydrates in Drug Design and Discovery.” In , edited by Jesus Jimenez-Barbero, F. Javier Canada, and Sonsoles Martin-Santamaria. RSC Drug Discovery. Cambridge: Royal Society of Chemistry. doi:10.1039/9781849739993.
Ogunsina, Makanjuola, Hangyi Pan, Pranati Samadder, Gilbert Arthur, and Frank Schweizer. 2013. “Structure Activity Relationships of N-Linked and Diglycosylated Glucosamine-Based Antitumor Glycerolipids.” Molecules (Basel, Switzerland) 18 (12). Multidisciplinary Digital Publishing Institute: 15288–304. doi:10.3390/molecules181215288.
Xu, Yaozu, Makanjuola Ogunsina, Pranati Samadder, Gilbert Arthur, and Frank Schweizer. 2013. “Structure-Activity Relationships of Glucosamine-Derived Glycerolipids: The Role of the Anomeric Linkage, the Cationic Charge and the Glycero Moiety on the Antitumor Activity.” ChemMedChem 8 (3): 511–20. doi:10.1002/cmdc.201200489.
Ogunsina, Makanjuola Pranati Samadder, Frank Schweizer, Gilbert Arthur, And Temilolu Idowu. 2015. “Di- and Tri-Cationic Glycosylated Antitumor Ether Lipids, L-Gucosylated GAELs and Rhamnose-Linked GAELs as Cytotoxic Agents against Epithelial Cancer Cells and Cancer Stem Cells.” https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015179983&recNum=161&docAn=CA2015050490&queryString=FP:(%22cancer%22) AND EN_ALL:nmr&maxRec=27681.
Arthur, Gilbert, Frank Schweizer, and Makanjuola Ogunsina. 2015. “Carbohydrates in Drug Design and Discovery.” In , edited by Jesus Jimenez-Barbero, F. Javier Canada, and Sonsoles Martin-Santamaria. RSC Drug Discovery. Cambridge: Royal Society of Chemistry. doi:10.1039/9781849739993.