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Substitution-Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate.
- 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.)
- Subjects :
- Animals
Fondaparinux
Glucuronidase metabolism
HCT116 Cells
Heparan Sulfate Proteoglycans pharmacology
Heparin metabolism
Humans
Nuclear Magnetic Resonance, Biomolecular
Oligosaccharides
Organoplatinum Compounds chemistry
Polysaccharides pharmacology
Heparitin Sulfate pharmacology
Organoplatinum Compounds pharmacology
Subjects
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