Poster Presentation 21st International Conference on Biological Inorganic Chemistry 2025

Strategies to improve cytotoxic properties of new anticancer dichloride platinum(II) complex (#514)

Adriana Kaszuba 1 , Karolina Pokrzywka 2 , Małgorzata Maj 2 , Janusz Dąbrowski 3 , Iwona Łakomska 1
  1. Chemistry Department, Nicolaus Copernicus University in Toruń, Toruń, Poland
  2. Department of Tissue Engineering, Collegium Medicum im. Ludwik Rydygier in Bydgoszcz; Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
  3. Chemistry Department, Jagiellonian University, Cracow, Poland

The high efficacy of cisplatin in treating various types of cancer, along with its numerous drawbacks (e.g., toxicity toward healthy cells, and high reactivity with glutathione), make searches analogs of this chemotherapeutic agent one of the key directions in the development of new anticancer drugs. Literature suggests that modification of the coordination sphere by incorporating heterocyclic ligands and/or exchanging chlorides with carboxylate ligands is a promising approach.1

The above literature data prompted us to synthesize dichloride platinum(II) complex containing triazole ligands with the general formula cis-[PtCl₂(bfte)₂] (1), where bfte- 1-(benzofuran-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethenone. The multinuclear magnetic resonance (1H, 13C, 15N, 195Pt NMR) and IR spectroscopy confirmed that the platinum(II) ion is coordinated monodentately by two N-donor ligands and two chloride ions in the cis position.

Lipophilicity, assessed using the classical shake-flask method, revealed that lipophilicity of (1) (logP = 1.12) is higher than cisplatin (logP = -2.31). Ellman's assay showed a lower reactivity of (1) with glutathione compared to cisplatin. The MTT assay revealed in vitro anticancer activity of (1) against bladder cancer cell lines (T24, 5637, HT1376)  (IC₅₀ = 5.00–8.50 µM), though it is 1.4 to 2.4 times less cytotoxic than cisplatin (IC₅₀ = 2.95–4.97 µM). The lower reactivity toward glutathione and a distinct mechanism of action suggests that (1) may bypass cisplatin-induced drug resistance, making (1) a promising therapeutic candidate. The favorable biological properties of (1), combined with its unsatisfactory in vitro cytotoxicity, prompted us to seek a solution through a dual approach (Fig. 1).

 

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Figure 1. Strategies to improve cytotoxic properties of complex (1)

Both applied strategies proved to be successful. Substitution of chlorides with an oxalate ligand resulted in approximately a fourfold increase in cytotoxicity against the same cancer cell lines (IC50 = 2.51 - 3.99 µM), while encapsulation enhanced cytotoxicity by up to eightfold (IC50 = 0.23 - 1.50 µM).

 

1. G. Facchetti, I. Rimoldi, Bioorg. Med. Chem. Lett., 2019, 29, 1257-1263