Assessment of Chemoselective Neoglycosylation Methods Using Chlorambucil as a Model

Goff, Randal D.; Thorson, Jon S.

doi:10.1021/jm101024j

Cited by 53 publications

(37 citation statements)

References 68 publications

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“…Several glucose-linked drugs designed to deliver attached therapeutics to tumours that overexpress a glucose transporter are also undergoing clinical evaluation or late preclinical development [171][172][173] . Most notably, glufosfamide -a glucose conjugate of iphosphoramide -has advanced to Phase III clinical trials (NCT01954992) 174 , in which it is being assessed for treatment of metastatic pancreatic cancer.…”

Section: Mip-1072mentioning

confidence: 99%

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Srinivasarao

Galliford

Low

2015

Nat Rev Drug Discov

577

502

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Most cancer drugs are designed to interfere with one or more events in cell proliferation or survival. As healthy cells may also need to proliferate and avoid apoptosis, anticancer agents can be toxic to such cells. To minimize these toxicities, strategies have been developed wherein the therapeutic agent is targeted to tumour cells through conjugation to a tumour-cell-specific small-molecule ligand, thereby reducing delivery to normal cells and the associated collateral toxicity. This Review describes the major principles in the design of ligand-targeted drugs and provides an overview of ligand-drug conjugates and ligand-imaging-agent conjugates that are currently in development.

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Section: Mip-1072mentioning

confidence: 99%

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Srinivasarao

Galliford

Low

2015

Nat Rev Drug Discov

577

502

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“…With aglycons lacking a convenient reductive amination connection point, further synthetic manipulation may be necessary to prepare a pharmacophore aglycon for coupling as exemplified via the use of tethered handles for betulinic acid neoglycosides 15 or alternative strategies as required for chlorambucil neoglycosides. 16 …”

Section: Section 2 - Chemical Aspects Of Neoglycosylationmentioning

confidence: 99%

Neoglycosylation and neoglycorandomization: enabling tools for the discovery of novel glycosylated bioactive probes and early stage leads

Goff

Thorson

2014

Med. Chem. Commun.

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This review focuses upon the development, scope, and utility of the highly versatile chemoselective alkoxyamine-based ‘neoglycosylation’ reaction first described by Peri and Dumy. The fundamentals of neoglycosylation and the subsequent development of a ‘neoglycorandomization’ platform to afford differentially-glycosylated libraries of plant-based natural products, microbial-based natural products, and small molecule-based drugs for drug discovery applications are discussed.

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“…[18] It was found that both polymer prodrugs exhibited dose-dependent inhibition of C26 and 4T1 cells. The doses of mPEG-poly(TMC-CL) required for 50% cytotoxicity (IC 50 ) against C26 and 4T1 cells were 39 and 1.2×10 2 μM respectively, which were ~2 fold higher than those for free CL (Figure 2b).…”

mentioning

confidence: 97%

Ring‐Opening Polymerization of Prodrugs: A Versatile Approach to Prepare Well‐Defined Drug‐Loaded Nanoparticles

Liu

Weitzhandler

et al. 2014

Angewandte Chemie

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We report a new methodology for the synthesis of polymer-drug conjugates from "compound"-all in one-prodrug monomers that consist of a cyclic polymerizable group that is appended to a drug through a cleavable linker. We show that organocatalyzed ring-opening polymerization can polymerize these monomers into well-defined polymer prodrugs that are designed to self-assemble into nanoparticles and release drug in response to a physiologically relevant stimulus. This method is compatible with structurally diverse drugs and allows different drugs to be copolymerized with quantitative conversion of the monomers. The drug loading can be controlled by adjusting the monomer(s) to initiator feed ratio and drug release can be encoded into the polymer by the choice of linker. Initiating these monomers from a polyethylene glycol macroinitiator yields amphiphilic diblock copolymers that spontaneously self-assemble into micelles with a long plasma circulation, which is useful for systemic therapy. KeywordsPolymerizable prodrug; Ring-opening polymerization; Polymer-drug conjugate; Nanoparticle; Cancer therapy Most small-molecule drugs utilized in the clinic have poor bioavailability and suboptimal pharmacokinetics because of their hydrophobicity and low molecular weight. Polymeric drug delivery systems can improve the efficacy of these drugs by increasing their water solubility, prolonging their circulation time, increasing the amount of drug deposited in the target tissue, and decreasing their exposure to normal tissues. [1] Conjugation of hydrophobic drugs to hydrophilic polymers can address these problems, [2] and is typically carried out by separate synthesis of the polymer, drug and linker, and sequential conjugation of the three entities to create the polymer-drug conjugate. This conventional strategy requires multiple reaction steps with limited yield, and has limited control of the site and degree of drug loading. New methods are hence needed to synthesize polymer-drug conjugates that have the following attributes: (1) are compatible with a structurally diverse set of drugs; (2) enable more than one drug to be conjugated to the same polymer with tunable control of the * chilkoti@duke.edu. Supporting information for this article is given via a link at the end of the document. Motivated by this rationale, we report herein a new method to synthesize polymer-drug conjugates by living ring-opening polymerization (ROP) of prodrugs (Scheme 1). This scheme inverts the conventional approach of conjugating a drug to a polymer post-synthesis, and instead directly incorporates the drug during synthesis of the polymer. These polymer prodrugs are composed of a "compound" monomer that consists of three covalently linked moieties: (1) a cyclic group that can undergo ROP to yield a biodegradable main chain, that is attached to (2) a cleavable linker, and which is attached to (3) a drug of interest. Living ROP of the compound monomer leads to the synthesis of a polymer with a biodegradable main chain with pendant drug molecules th...

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Assessment of Chemoselective Neoglycosylation Methods Using Chlorambucil as a Model

Cited by 53 publications

References 68 publications

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Neoglycosylation and neoglycorandomization: enabling tools for the discovery of novel glycosylated bioactive probes and early stage leads

Ring‐Opening Polymerization of Prodrugs: A Versatile Approach to Prepare Well‐Defined Drug‐Loaded Nanoparticles

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