Advances in the development of hybrid anticancer drugs

Fortin, Sébastien; Bérubé, Gervais

doi:10.1517/17460441.2013.798296

Cited by 196 publications

(152 citation statements)

References 67 publications

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“…72,79,80 More so, as an emerging area in drug development, the hybrid concept is beset with initial challenges that are not remarkably unexpected of any new field of endeavor. For instance, the physicochemical properties of most hybrid drugs, owing to their large molecular weight, are highly unpredictable and they tend to deviate from the generally acknowledged drug-like properties of medicinal agents.…”

Section: Limitationsmentioning

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: Limitationsmentioning

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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“…A number of molecules of this type have been described in previous reviews [8,9]. Since DNA topoisomerases I and II (topo I and II) are recognized as the primary targets of well-established antitumour drugs, hybrid compounds containing topo I/topo II inhibitors have been explored.…”

Section: Hybrid Compounds Incorporating Cytotoxic Agentsmentioning

confidence: 99%

Perspectives in the development of hybrid bifunctional antitumour agents

Musso

Dallavalle

Zunino

2015

Biochemical Pharmacology

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In spite of the development of a large number of novel target-specific antitumour agents, the single-agent therapy is in general not able to provide an effective durable control of the malignant process. The limited efficacy of the available agents (both conventional cytotoxic and novel target-specific) reflects not only the expression of defence mechanisms, but also the complexity of tumour cell alterations and the redundancy of survival pathways, thus resulting in tumour cell ability to survive under stress conditions. A well-established strategy to improve the efficacy of antitumour therapy is the rational design of drug combinations aimed at achieving synergistic effects and overcoming drug resistance. An alternative strategy could be the use of agents designed to inhibit simultaneously multiple cellular targets relevant to tumour growth/survival. Among these novel agents are hybrid bifunctional drugs, i.e. compounds resulting by conjugation of different drugs or containing the pharmocophores of different drugs. This strategy has been pursued using various conventional or target-specific agents (with DNA damaging agents and histone deacetylase inhibitors as the most exploited compounds). A critical overview of the most representative compounds is provided with emphasis on the HDAC inhibitor-based hybrid agents. In spite of some promising results, the actual pharmacological advantages of the hybrid agents remain to be defined. This commentary summarizes the recent advances in this field and highlights the pharmacological basis for a rational design of hybrid bifunctional agents.

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“…Class I: chimeric/hybrid pharmacophore designs Hybrid anticancer agents are of great therapeutic interest as they can potentially overcome most of the pharmacokinetic drawbacks encountered when using conventional anticancer drugs (Fortin and Berube, 2013). A chemical entity constituting two structural domains, depicting dissimilar action as an outcome of acting through different modes of actions are called as hybrid drugs, thus indicating that a hybrid molecule acts as two distinct pharmacophores.…”

Section: Classificationmentioning

confidence: 99%

“…A chemical entity constituting two structural domains, depicting dissimilar action as an outcome of acting through different modes of actions are called as hybrid drugs, thus indicating that a hybrid molecule acts as two distinct pharmacophores. Hybrid anticancer drugs are designed on the basis of combining a haptophoric moiety or merging two or more drugs (Fortin and Berube, 2013;Hulsman et al, 2007). Ko et al recently revealed and synthesized the hybrid histone deacetylase (HDAC) inhibitor and c-Src inhibitor (non-receptor tyrosine kinase) (Ko et al, 2013).…”

Section: Classificationmentioning

confidence: 99%

“…During the course of preparing the present manuscript, reviews by Nepali et al, Bansal et al, and Fortin et al, which covered the approaches and strategies on hybrids drugs were published (Bansal and Silakari, 2014;Fortin and Berube, 2013;Nepali et al, 2014). In 2007, Junior et al, (Viegas-Junior et al, 2007 and Gediya and Njar (Gediya and Njar, 2009) in 2009 also made successful attempts to compile a review on the design of hybrid anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

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