Substitution-Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate.
Anil Kumar GorleSamantha J KatnerWyatt E JohnsonDaniel E LeeA Gerard DanielEric P GinsburgMark von ItzsteinSusan J Berners-PriceNicholas P FarrellPublished in: Chemistry (Weinheim an der Bergstrasse, Germany) (2018)
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.
Keyphrases
- cell cycle arrest
- induced apoptosis
- endothelial cells
- cell death
- case control
- molecular docking
- pi k akt
- endoplasmic reticulum stress
- signaling pathway
- density functional theory
- venous thromboembolism
- high throughput
- dna binding
- oxidative stress
- cell proliferation
- molecular dynamics simulations
- transcription factor
- induced pluripotent stem cells
- single cell