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

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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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.

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

Bibliographical note

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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.

Keywords

antitumor agents
glycoconjugates
metallohelices
nuclear delivery
self-assembly

ASJC Scopus subject areas

Chemistry(all)
Catalysis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/anie.202006814Licence: CC BY

PublishedFinal published version, 5.5 MBLicence: CC BY

Cite this

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 ed. in English), 59(34), 14677-14685. https://doi.org/10.1002/anie.202006814

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

In: Angewandte Chemie (International ed. in English), Vol. 59, No. 34, 17.08.2020, p. 14677-14685.

Research output: Contribution to journal › Article › peer-review

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 ed. in English), vol. 59, no. 34, pp. 14677-14685. https://doi.org/10.1002/anie.202006814

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. / Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo. In: Angewandte Chemie (International ed. in English). 2020 ; Vol. 59, No. 34. pp. 14677-14685.

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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.",

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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

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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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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