Cytotoxic properties of d-gluco-, d-galacto- and d-manno-configured 2-amino-2-deoxy-glycerolipids against epithelial cancer cell lines and BT-474 breast cancer stem cells

Samadder, Pranati; Xu, Yaozu; Schweizer, Frank; Arthur, Gilbert

doi:10.1016/j.ejmech.2014.03.057

Cited by 21 publications

(54 citation statements)

References 33 publications

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“…[23][24][25]155,156 With the recent reports of GAEL analogs as one of the very few agents capable of killing cancer stem cells (CSCs), 42 perhaps due to their apoptosis-independent mechanism of action, combining GAELs with other agents that can shrink the bulk tumor mass could be a promising avenue to develop novel therapeutics. The potentials of GDGs to overcome these twin-problem in cancer treatment, especially with the more potent triamino analog, may present an alternative regimen in cancer management if successful.…”

Section: Discussionmentioning

confidence: 99%

“…The biological evaluations of various Sand N-glycosidic analogs of 1 show very little to no promise, as there was significant (3-to 5-fold) loss of activity across all cell lines tested. 42,44 Gratifyingly, the C-analogs displayed cytotoxic activities comparable to the reference O-glycoside, but its synthetic approach is an arduous task and may not be economically viable on a large scale. 45,46 Nonetheless, they potentially represent a better choice for pre-clinical studies as they will not be susceptible to hydrolysis by glycosidases in vivo.…”

Section: Structure-activity Relationships (Sar)mentioning

confidence: 99%

“…39 Mechanistic studies demonstrated that GAELs kill cells via an apoptosis-independent mechanism which may involve perturbation of the endocytic pathway and release of cathepsins to mediate cell death independent of apoptosis. 34,40,41 Despite the initial development of GAELs being staggered and non-systematic, the identification of glucosamine-derived non-phosphorus analog 1 and their recent demonstration of cytotoxicity against breast cancer stem cells, 42 have provided the needed impetus to unravel the pharmacophore responsible for their cytotoxicity. …”

Section: Glycosylated Antitumor Ether Lipidsmentioning

confidence: 99%

“…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. 42 Diglycosylated GAEL analog (Figure 1-2) has also been investigated to evaluate the effects of additional glucosamine moiety in the structure. 44 The hypothesis that an additional glucosamine moiety will enhance anticancer activities is based on the analogs of GAELs will display in vivo activity.…”

Section: Structure-activity Relationships (Sar)mentioning

confidence: 99%

“…In light of the non-apoptotic mechanism of cell death induced by GDG 1 relative to other clinically-used anticancer agents, 34 their reported cytotoxicity against cancer stem cells, 42 the development of resistance to clinically-used pro-apoptotic agents by cancer cells, 15,111 the challenges associated with combination cocktails, 70,72 and the potentials of nonapoptosis-inducing cytotoxic drugs in the fight against cancer; we conceived that a hybrid molecule comprising 1, with an apoptosis-inducing anticancer molecule could present two separately functioning domains that may trigger two or more cytocidal mechanistic pathways to inhibit tumor growth more effectively than either compound alone.…”

Section: Hypothesismentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Structure-activity Relationships (Sar)mentioning

confidence: 99%

Section: Glycosylated Antitumor Ether Lipidsmentioning

confidence: 99%

Section: Structure-activity Relationships (Sar)mentioning

confidence: 99%

Section: Hypothesismentioning

confidence: 99%

See 3 more Smart Citations

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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Recent Advances in Stereocontrolled Mannosylation: Focus on Glycans Comprising Acidic and/or Amino Sugars

Alex

Demchenko

2021

The Chemical Record

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The main focus of this review is to describe accomplishments made in the stereoselective synthesis of β‐linked mannosides functionalized with carboxyls or amines/amides. These ManNAc, ManA and ManNAcA residues found in many glycoconjugates, bacterial polysaccharides, and alginates have consistently captured interest of the glycoscience community both due to synthetic challenge and therapeutic potential.

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Synthesis and cytotoxicity of fused thiophene and pyrazole derivatives derived from 2-N-acetyl-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene

2014

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The reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo [b]thiophene with chloroacetyl chloride gave the 2-chloroacetamido derivative 3. The latter reacted with hydrazine hydrate to give the hydrazine derivative 5 which was used to form the hydrazone derivatives 7a, b and 9a, b via its reaction with some carbonyl compounds. Moreover, it produced the pyrazole derivatives 11a, b through its reaction with either acetylacetone or ethyl acetoacetate. On the other hand, compounds 5 and 3 were used to form some thiazole, pyridine, and fused derivatives. The cytotoxicity of the newly obtained products was evaluated against some of the human cancer and normal cell lines where the results showed that compounds 3, 11b, 13, 18c, 18d, 21, 23, and 24 exhibited optimal cytotoxic effect against cancer cell lines, with IC 50 's in the nM range.

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Cytotoxic properties of d-gluco-, d-galacto- and d-manno-configured 2-amino-2-deoxy-glycerolipids against epithelial cancer cell lines and BT-474 breast cancer stem cells

Cited by 21 publications

References 33 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

Recent Advances in Stereocontrolled Mannosylation: Focus on Glycans Comprising Acidic and/or Amino Sugars

Synthesis and cytotoxicity of fused thiophene and pyrazole derivatives derived from 2-N-acetyl-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene

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