Cytotoxic and antiparasitic activities of diphosphine-metal complexes of group 10 containing acylthiourea as ligands

Abstract

In this work, group 10 transition metal complexes bearing dppe [1,2-bis(diphenylphosphino)ethane] and acylthiourea ligands were evaluated for their cytotoxic and antiparasitic activities. Six new complexes with a general formula [M(L_n)(dppe)]BF₄ [where M = Ni^II, Pd^II or Pt^II; L_n = N, N'-dimethyl-N-benzoyl thiourea (L₁) or N, N'-dimethyl-N-tiofenyl thiourea (L₂) were synthesized and characterized by infrared, NMR (³¹P{¹H}, ¹H and ¹³C{¹H}) spectroscopies, elemental analysis and molar conductivity. The structures of the complexes were confirmed by X-ray diffraction technique. The biological activity of the complexes was evaluated on breast cancer cells (MDA-MB-231 and MCF-7) and causative agents of chagas disease and leishmaniasis. The complexes presented higher cytotoxicity for breast cancer cell lines compared to non-tumor cells. Nickel complexes stood out when evaluated against the triple-negative breast cancer line (MDA-MB-231), presenting considerably lower IC₅₀ values (about 10 to 22×), when compared to palladium and platinum complexes, and the cisplatin drug. When evaluated on the triple-negative line (MDA-MB-231), the complexes [Ni(L₂)(dppe)]BF₄(2), [Pd(L₂)(dppe)]BF₄(4) and [Pt(L₂)(dppe)]BF₄(6) were able to induce cell morphological changes, influence on the cell colony formation and the size of the cells. The complexes inhibit cell migration and cause changes to the cell cytoskeleton and nuclear arrangement. In the same cell line, the compounds caused cell arrest in the Sub-G1 phase of the cell cycle. The compounds were also tested against the Trypanosom Cruzi (T. cruzi) and Leishmania sp. parasites, which cause Chagas and leishmaniasis disease, respectively. The compounds showed good anti-parasitic activity, mainly for T. cruzi, with lower IC₅₀ values, when compared to the commercial drug, benznidazole. The compounds interact with CT-DNA, indicating that interaction occurs by the minor groove of the biomolecule.

Keywords: Acylthiourea; Breast cancer; Chagas disease; Leishmaniasis; Metal complexes; Phosphine.