Synthesis and characterisation of sterically hindered pyridine based multinuclear platinum anticancer complexes and their cytotoxicity

Background: Multinuclear platinum drugs, such as BBR3464, are of current interest due to their higher activity compared to cisplatin and their retained activity in cisplatin resistant cells. They are however extremely toxic and susceptible to degradation. A current drug undergoing clinical trials, picoplatin, has a sterically hindered platinum centre reducing susceptibility to deactivation and degradation. Combining these strengths could produce highly active drugs that overcome drug resistance, while resistant to deactivation and degradation.

Aim: To synthesise novel sterically hindered pyridine based multinuclear platinum anticancer complexes that are highly cytotoxic in platinum resistant cancer cells and resistant to degradation.

Method: The bispyridine ligands were synthesised via a peptide coupling reaction using isonicotinic acids and varying length diaminoalkanes. Reacting with transplatin yielded a range of multinuclear platinum complexes. Characterisation was by standard chemical spectroscopy. Cytotoxicity studies were performed against a panel of cancer cell lines and binding kinetics with biological nucleophiles such as glutathione and human serum albumin.

Results: Multinuclear platinum complexes were synthesised with various variable length bispyridine bridging ligands. Cytotoxicity assays showed high activity against several cancer cell lines and platinum binding kinetics showed decreased reactivity with biological nucleophiles.

Conclusions: Sterically hindered multinuclear platinum complexes show potential as anticancer drugs due to their potent anticancer effects and lowered deactivation and degradation.