Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL) – hybrids
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Date
2015-07-17
Authors
Idowu, Temilolu
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Abstract
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 GAEL–chlorambucil 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)
Description
Keywords
amphiphile, antitumor agent, cationic lipid, chlorambucil-linked hybrid, cytotoxic lipid, glycolipid, hybrid drug, drug design
Citation
Idowu, T. et al., Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)-chlorambucil-hybrids, Chem. Phys. Lipids (2015), http://dx.doi.org/10.1016/j.chemphyslip.2015.07.003