Substitution-Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate

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Gorle, Anil Kumar
Katner, Samantha J
Johnson, Wyatt E
Lee, Daniel E
Daniel, A Gerard
Ginsburg, Eric P
von Itzstein, Mark
Berners-Price, Susan J
Farrell, Nicholas P
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2018
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Abstract

Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumour‐related events including angiogenesis, cell invasion, and metastasis. Metalloshielding of heparan sulfate (HS) by positively charged polynuclear platinum complexes (PPCs) effectively inhibits physiologically critical HS functions. Studies using bacterial P. heparinus heparinase II showed that a library of Pt complexes varying in charge and nuclearity and the presence or absence of a dangling amine inhibits the cleavage activity of the enzyme on the synthetic pentasaccharide, Fondaparinux (FPX). Charge‐dependent affinity of PPC for FPX was seen in competition assays with methylene blue and ethidium bromide. The dissociation constant (Kd) of TriplatinNC for FPX was directly measured by isothermal titration calorimetry (ITC). The trend in DFT calculated interaction energies with heparin fragments is consistent with the spectroscopic studies. Competitive inhibition of TAMRA‐R9 internalization in human carcinoma (HCT116) cells along with studies in HCT116, wildtype CHO and mutant CHO‐pgsA745 (lacking HS/CS) cells confirm that HSPG‐mediated interactions play an important role in the cellular accumulation of PPCs.

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Chemistry - A European Journal

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24

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25

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DP150100308

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© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is the peer reviewed version of the following article: Substitution‐Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate, Chemistry - A European Journal, Volume 24, Issue 25, Pages 6606-6616, 2018, which has been published in final form at https://doi.org/10.1002/chem.201706030. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving (http://olabout.wiley.com/WileyCDA/Section/id-828039.html)

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Chemical sciences

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