Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo

Monosaccharides are added to the hydrophilic face of a self‐assembled asymmetric FeII metallohelix, using CuAAC chemistry. The sixteen resulting architectures are water‐stable and optically pure, and exhibit improved antiproliferative selectivity against colon cancer cells (HCT116 p53+/+) with respe...

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Veröffentlicht in:Angewandte Chemie International Edition Jg. 59; H. 34; S. 14677 - 14685
Hauptverfasser: Song, Hualong, Allison, Simon J., Brabec, Viktor, Bridgewater, Hannah E., Kasparkova, Jana, Kostrhunova, Hana, Novohradsky, Vojtech, Phillips, Roger M., Pracharova, Jitka, Rogers, Nicola J., Shepherd, Samantha L., Scott, Peter
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Germany Wiley Subscription Services, Inc 17.08.2020
John Wiley and Sons Inc
Ausgabe:International ed. in English
Schlagworte:
antitumor agents
Cisplatin
Colon
Colon cancer
Colorectal cancer
Conjugation
Deoxyribonucleic acid
DNA
Enantiomers
Glucose
Glucose transporter
glycoconjugates
Glycoconjugates - chemistry
HCT116 Cells
Humans
metallohelices
Metals - chemistry
Monosaccharides
Neoplasms - pathology
nuclear delivery
p53 Protein
Proton Magnetic Resonance Spectroscopy
Selectivity
self-assembly
Spectrometry, Mass, Electrospray Ionization
Tumors
Weight loss
self-assembly
nuclear delivery
metallohelices
glycoconjugates
antitumor agents
ISSN:1433-7851, 1521-3773, 1521-3773
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Zusammenfassung:Monosaccharides are added to the hydrophilic face of a self‐assembled asymmetric FeII metallohelix, using CuAAC chemistry. The sixteen resulting architectures are water‐stable and optically pure, and exhibit improved antiproliferative selectivity against colon cancer cells (HCT116 p53+/+) with respect to the non‐cancerous ARPE‐19 cell line. While the most selective compound is a glucose‐appended enantiomer, its cellular entry is not mainly glucose transporter‐mediated. Glucose conjugation nevertheless increases nuclear delivery ca 2.5‐fold, and a non‐destructive interaction with DNA is indicated. Addition of the glucose units affects the binding orientation of the metallohelix to naked DNA, but does not substantially alter the overall affinity. In a mouse model, the glucose conjugated compound was far better tolerated, and tumour growth delays for the parent compound (2.6 d) were improved to 4.3 d; performance as good as cisplatin but with the advantage of no weight loss in the subjects. Asymmetric triplex metallohelices can be conjugated with sugars using post‐assembly CuAAC chemistry, to give optically pure architectures with anti‐cancer activity and marked selectivity with respect to non‐cancerous cell lines. Glucose‐appended structures exhibit improved nuclear uptake in vitro and supress tumour growth in vivo.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.202006814