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

Hualong Song; Simon J. Allison; Viktor Brabec; Hannah E. Bridgewater; Jana Kasparkova; Hana Kostrhunova; Vojtech Novohradsky; Roger M. Phillips; Jitka Pracharova; Nicola J. Rogers; Samantha L. Shepherd; Peter Scott

doi:10.1002/anie.202006814

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

Hualong Song, Simon J. Allison, Viktor Brabec^*, Hannah E. Bridgewater, Jana Kasparkova, Hana Kostrhunova, Vojtech Novohradsky, Roger M. Phillips^*, Jitka Pracharova, Nicola J. Rogers^*, Samantha L. Shepherd, Peter Scott^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Journal article › peer-review

16 Citations (Scopus)

Abstract

Monosaccharides are added to the hydrophilic face of a self-assembled asymmetric Fe^II 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.

Original language	English
Pages (from-to)	14677-14685
Number of pages	9
Journal	Angewandte Chemie - International Edition
Volume	59
Issue number	34
DOIs	https://doi.org/10.1002/anie.202006814
Publication status	Published - 17 Aug 2020

User-Defined Keywords

antitumor agents
glycoconjugates
metallohelices
nuclear delivery
self-assembly

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10.1002/anie.202006814

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Song, H., Allison, S. J., Brabec, V., Bridgewater, H. E., Kasparkova, J., Kostrhunova, H., Novohradsky, V., Phillips, R. M., Pracharova, J., Rogers, N. J., Shepherd, S. L., & Scott, P. (2020). Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo. Angewandte Chemie - International Edition, 59(34), 14677-14685. https://doi.org/10.1002/anie.202006814

@article{f7b502ecaf354c448df779d59f604afe,

title = "Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo",

abstract = "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.",

keywords = "antitumor agents, glycoconjugates, metallohelices, nuclear delivery, self-assembly",

author = "Hualong Song and Allison, {Simon J.} and Viktor Brabec and Bridgewater, {Hannah E.} and Jana Kasparkova and Hana Kostrhunova and Vojtech Novohradsky and Phillips, {Roger M.} and Jitka Pracharova and Rogers, {Nicola J.} and Shepherd, {Samantha L.} and Peter Scott",

note = "Funding information: We thank the Warwick's Institute of Advanced Study for an Early Career Fellowship (HS). V.B., J.K., H.K., V.N. and J.P. acknowledge the support from the Czech Science Foundation, Grant 18-09502S. R.P. acknowledges University Research Funding from the University of Huddersfield to support multidisciplinary research. Publisher Copyright: {\textcopyright} 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.",

year = "2020",

month = aug,

day = "17",

doi = "10.1002/anie.202006814",

language = "English",

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Song, H, Allison, SJ, Brabec, V, Bridgewater, HE, Kasparkova, J, Kostrhunova, H, Novohradsky, V, Phillips, RM, Pracharova, J, Rogers, NJ, Shepherd, SL & Scott, P 2020, 'Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo', Angewandte Chemie - International Edition, vol. 59, no. 34, pp. 14677-14685. https://doi.org/10.1002/anie.202006814

TY - JOUR

T1 - Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo

AU - Song, Hualong

AU - Allison, Simon J.

AU - Brabec, Viktor

AU - Bridgewater, Hannah E.

AU - Kasparkova, Jana

AU - Kostrhunova, Hana

AU - Novohradsky, Vojtech

AU - Phillips, Roger M.

AU - Pracharova, Jitka

AU - Rogers, Nicola J.

AU - Shepherd, Samantha L.

AU - Scott, Peter

N1 - Funding information: We thank the Warwick's Institute of Advanced Study for an Early Career Fellowship (HS). V.B., J.K., H.K., V.N. and J.P. acknowledge the support from the Czech Science Foundation, Grant 18-09502S. R.P. acknowledges University Research Funding from the University of Huddersfield to support multidisciplinary research. Publisher Copyright: © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

PY - 2020/8/17

Y1 - 2020/8/17

N2 - 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.

AB - 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.

KW - antitumor agents

KW - glycoconjugates

KW - metallohelices

KW - nuclear delivery

KW - self-assembly

UR - http://www.scopus.com/inward/record.url?scp=85087621111&partnerID=8YFLogxK

U2 - 10.1002/anie.202006814

DO - 10.1002/anie.202006814

M3 - Journal article

C2 - 32489012

AN - SCOPUS:85087621111

SN - 1433-7851

VL - 59

SP - 14677

EP - 14685

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 34

ER -

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

Abstract

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