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Pincer-dipeptide and pseudodipeptide conjugates: Synthesis and bioactivity studies.
Svetlana G Churusova1, Diana V Aleksanyan1, Ekaterina Yu Rybalkina2
1A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow 119991, Russia.
Journal of Inorganic Biochemistry
|August 9, 2022
Summary
New palladium (Pd) pincer complexes derived from dipeptides show significant antitumor activity, comparable to cisplatin, and can overcome drug resistance in cancer cells.
Area of Science:
- Medicinal Chemistry
- Organometallic Chemistry
- Cancer Research
Background:
- Pincer scaffolds are increasingly used for developing metal-based anticancer agents.
- Dipeptide and dipeptide surrogate ligands offer novel structural possibilities for metal complexes.
Purpose of the Study:
- To design and synthesize novel palladium (Pd) pincer complexes using dipeptides and dipeptide surrogates.
- To evaluate the cytotoxic and antiproliferative activities of these Pd complexes against various cancer cell lines.
- To investigate the mechanism of action and drug resistance-overcoming potential of the synthesized complexes.
Main Methods:
- Synthesis of nonclassical pincer ligands based on picolinylamides with S-donor amino acid residues.
- Site-selective direct cyclopalladation under mild conditions to form Pd(II) pincer complexes.
- Characterization using NMR (1H, 13C, 31P, 2D NMR) and IR spectroscopy, and X-ray crystallography.
- Cytotoxicity screening against cancer cell lines and noncancerous cells, including drug-resistant lines.
- Apoptosis induction, mitochondrial function, and DNA/protein binding studies.
Main Results:
- Pd(II) pincer complexes were synthesized in good to high yields.
- S,N,N-coordination was confirmed through spectroscopic and crystallographic analyses.
- Several complexes exhibited significant cytotoxicity comparable to cisplatin.
- Homocysteine-based derivatives showed efficacy against doxorubicin-resistant cells, suggesting a way to overcome drug resistance.
- Complexes induced apoptosis but did not affect mitochondria.
- Comparative binding studies indicated advantages of pincer-(pseudo)dipeptide conjugates over monoamino acid prototypes.
Conclusions:
- Novel palladium pincer complexes based on dipeptides and their surrogates are effective anticancer agents.
- These complexes demonstrate potential in overcoming multidrug resistance in cancer therapy.
- The structural features of these ligands contribute to their potent biological activity and DNA/protein binding capabilities.
