The interactions of two organoplatinum complexes, [Pt(C^N)Cl(dppa)], 1, and [Pt(C^N)Cl(dppm)], 2 (C^N = N(1), C(2')-chelated, deprotonated 2-phenylpyridine, dppa = bis(diphenylphosphino)amine, dppm = bis(diphenylphosphino)methane), as antitumor agents, with bovine serum albumin (BSA) and human serum albumin (HSA) have been studied by fluorescence and UV-vis absorption spectroscopic techniques at pH 7.40. The quenching constants and binding parameters (binding constants and number of binding sites) were determined by fluorescence quenching method. The obtained results revealed that there is a strong binding interaction between the ligands and proteins. The calculated thermodynamic parameters (ΔG, ΔH, and ΔS) confirmed that the binding reaction is mainly entropy-driven, and hydrophobic forces played a major role in the reaction. The displacement experiment shows that these Pt complexes can bind to the subdomain IIA (site I) of albumin. Moreover, synchronous fluorescence spectroscopy studies revealed some changes in the local polarity around the tryptophan residues. Finally, the distance, r, between donor (serum albumin) and acceptor (Pt complexes) was obtained according to Förster theory of nonradiation energy transfer.

New complexes [Pt(C^N)Cl(dppa)], 1, and [Pt(C^N)Cl(dppm)], 2, C^N, deprotonated 2-phenylpyridine; dppa, bis(diphenylphosphino)amine; dppm, bis(diphenylphosphino)methane, were suggested to have penta-coordinated geometry, as investigated by NMR and conductometry. Pharmacological effects of 1 and 2 were evaluated for their proteasome-inhibitory and apoptosis-inducing activities under in vitro and in vivo conditions, showing significant proteasome-inhibitory activity against purified 20S proteasome, while 2 demonstrated superior inhibitory activity against cellular 26S proteasome. Consistently, this effect was associated with higher levels of proteasome target proteins and apoptosis induction in breast cancer cells. Importantly, preliminary studies show 1 and 2 were able to exert a similar effect in vivo by inhibiting the growth of breast cancer xenografts in mice, which was associated with proteasome inhibition and apoptosis induction. Interaction of 1 and 2 with herring sperm DNA was investigated by fluorimeteric emission suggesting that PtII-containing biphosphine complexes with DNA binding capabilities can also target and inhibit the tumor proteasome.

No abstract

No abstract

No abstract