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 journalArticlepeer-review

10 Citations (Scopus)
22 Downloads (Pure)

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 languageEnglish
Pages (from-to)14677-14685
Number of pages9
JournalAngewandte Chemie (International ed. in English)
Volume59
Issue number34
DOIs
Publication statusPublished - 17 Aug 2020
Externally publishedYes

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

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