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

Authors :
Gorle AK
Katner SJ
Johnson WE
Lee DE
Daniel AG
Ginsburg EP
von Itzstein M
Berners-Price SJ
Farrell NP
Source :
Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2018 May 02; Vol. 24 (25), pp. 6606-6616. Date of Electronic Publication: 2018 Apr 14.
Publication Year :
2018

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 (K <subscript>d</subscript> ) 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-R <subscript>9</subscript> 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.<br /> (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Details

Language :
English
ISSN :
1521-3765
Volume :
24
Issue :
25
Database :
MEDLINE
Journal :
Chemistry (Weinheim an der Bergstrasse, Germany)
Publication Type :
Academic Journal
Accession number :
29655185
Full Text :
https://doi.org/10.1002/chem.201706030