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Updated: Feb 11, 2026
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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
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Substitution-Inert Polynuclear Platinum Complexes as Metalloshielding Agents for Heparan Sulfate
Anil Kumar Gorle1, Samantha J Katner2, Wyatt E Johnson2
1Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland, 4222, Australia.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|April 15, 2018
Summary
Positively charged platinum complexes (PPCs) inhibit heparanase, an enzyme crucial for tumor growth and spread. These complexes bind to heparan sulfate, blocking its function and impacting cancer cell interactions.
Area of Science:
- Biochemistry
- Cancer Biology
- Materials Science
Background:
- Heparan sulfate proteoglycans (HSPGs) play a key role in tumor progression, including angiogenesis, invasion, and metastasis.
- Heparanase enzyme activity is critical for these tumor-related events.
- Positively charged polynuclear platinum complexes (PPCs) can metalloshield heparan sulfate (HS), inhibiting its functions.
Purpose of the Study:
- To investigate the inhibitory effect of PPCs on heparanase activity.
- To elucidate the mechanism of PPC interaction with heparan sulfate.
- To assess the role of HSPG-mediated interactions in the cellular uptake of PPCs.
Main Methods:
- Enzyme inhibition assays using bacterial P. heparinus heparinase II and the synthetic pentasaccharide Fondaparinux (FPX).
- Spectroscopic competition assays (methylene blue, ethidium bromide) to determine charge-dependent affinity.
- Isothermal titration calorimetry (ITC) to measure the dissociation constant (Kd) of TriplatinNC for FPX.
- Density Functional Theory (DFT) calculations of interaction energies with heparin fragments.
- Cellular uptake studies in human carcinoma (HCT116) and Chinese hamster ovary (CHO) cells (wildtype and HS/CS deficient mutant CHO-pgsA745).
Main Results:
- A library of PPCs, varying in charge and nuclearity, inhibited heparanase cleavage of FPX.
- Charge-dependent affinity of PPCs for FPX was observed.
- The dissociation constant (Kd) of TriplatinNC for FPX was determined by ITC.
- DFT calculations supported spectroscopic findings regarding interactions with heparin fragments.
- HSPG-mediated interactions were confirmed to be important for PPC cellular accumulation.
Conclusions:
- Positively charged polynuclear platinum complexes effectively inhibit heparanase activity.
- The interaction between PPCs and heparan sulfate is charge-dependent and plays a significant role in cellular uptake.
- PPCs show potential as inhibitors of tumor-related events mediated by heparan sulfate.
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