Design, synthesis and biological evaluation of estradiol–chlorambucil hybrids as anticancer agents

Gupta, Atul; Saha, Pijus; Descôteaux, Caroline; Leblanc, Valérie; Asselin, Éric; Bérubé, Gervais

doi:10.1016/j.bmcl.2010.01.053

Cited by 52 publications

(44 citation statements)

References 28 publications

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“…A previous study also reported this high CC 50 value of chlorambucil. 128 Compounds 3 and 4 proved to be the most active hybrids against all the cell lines with the exception of MiaPaCa2. The activities of 3 and 4 were quite similar against these cell lines, the only exception being with DU145 cells where 3 was almost twice as active as 4 with a CC 50 of 6.0 µM for 3 versus 11.0 µM for 4.…”

Section: Cytotoxicitymentioning

confidence: 99%

“…The mechanism of action of alkylating agents involves the formation of adducts with DNA, RNA and proteins which ultimately leads to apoptotic cell death. 125 Furthermore, the ability to couple chlorambucil to other moieties without losing its inherent activity [126][127][128] made it an attractive molecule to explore the hybrid concept. In the studies described herein, we a) explored the cytotoxic effects of chlorambucil-linked GAEL hybrids b) investigated the contribution of chlorambucil to the overall activity and c) investigated the significance of a cationic charge on the activity of the hybrid molecule against cancer cell lines.…”

Section: Introductionmentioning

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: Cytotoxicitymentioning

confidence: 99%

Section: Introductionmentioning

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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“…These exhibited potent inhibitory activity against the hormone-dependent LNCaP (androgen-sensitive human prostate adenocarcinoma cells derived from the left supraclavicular lymph node) cancer cell lines and PC3 cell lines. MDA-MB-231) breast cancer cell lines (Gupta et al, 2010).…”

Section: Classificationmentioning

confidence: 99%

A review on pharmacophoric designs of antiproliferative agents

et al. 2014

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“…[1][2][3] In recent years, significant research efforts have been made in the development of various CHL derivatives with improved selectivity and high antitumor activity. [4,5] In this regard, it will be beneficial to develop new CHL-based theranostic probes and utilize its antitumor properties in combination with magnetic resonance imaging (MRI) and therapy. MRI is a powerful diagnostic imaging modality and is superior over other imaging techniques due to its non-invasiveness, non-ionizing radiation, and high spatial resolution.…”

mentioning

confidence: 99%

Synthesis, characterization, and relaxation studies of Gd‐DO3A conjugate of chlorambucil as a potential theranostic agent

et al. 2017

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DO3A‐based macrocycles serve as attractive templates from which clinically useful theranostic agents can be obtained after coupling with molecular targeted therapeutic drugs. In this study, we describe the chemical synthesis, relaxation, and cytotoxicity studies of a new DO3A conjugate of chlorambucil (CHL) as a magnetic resonance imaging (MRI) theranostic agent. A convenient route of synthesis is reported, which allowed conjugation of the macrocyclic ligand (DO3A) to the chemotherapeutic drug (CHL) via tyrosine for the preparation of an attractive chelate‐drug ensemble (DO3A‐TR‐CHL). The structures of all intermediates and final compound have been determined by 1H, 13C NMR, and MS. The efficacy of DO3A‐TR‐CHL as a non‐ionic magnetic contrast agent was tested by performing relaxometric studies on its gadolinium complex. The complex exhibited relaxivities (7.11 mm−1/s) higher than that of currently used MR contrast agents and showed enhanced contrast in T1‐weighted images. MTT assays revealed that both DO3A‐TR‐CHL and Gd(III)‐DO3A‐TR‐CHL conjugates exhibited dose‐dependent toxicity and an enhanced antiproliferative activity against tumor (A549 and HeLa) cell lines compared to that of parent drug (CHL), thereby demonstrating their potential to be used as a magnetic resonance imaging theranostic for improved molecular imaging and therapy of human cancers.

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Design, synthesis and biological evaluation of estradiol–chlorambucil hybrids as anticancer agents

Cited by 52 publications

References 28 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

A review on pharmacophoric designs of antiproliferative agents

Synthesis, characterization, and relaxation studies of Gd‐DO3A conjugate of chlorambucil as a potential theranostic agent

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