首页|Distinct mechanism of action for antitumoral neutral cyclometalated Pt (II)-complexes bearing antifungal imidazolyl-based drugs

Distinct mechanism of action for antitumoral neutral cyclometalated Pt (II)-complexes bearing antifungal imidazolyl-based drugs

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  • NSTL
  • Elsevier
Three neutral Pt(II) complexes containing 1-Methylimidazole and the antifungal imidazolyl drugs Clotrimazole and Bifonazole have been prepared. The general formula of the new derivatives is [Pt(kappa(2)-(C<^>N)Cl(L)], where C<^>N stands for ppy = 2-phenylpyridinate, and L = 1-Methylimidazole (MeIm) for [Pt-MeIm]; L = Clotrimazole (CTZ) for [Pt-CTZ] and L = Bifonazole (BFZ) for [Pt-BFZ]). The complexes have been completely characterized in solution and the crystal structures of [Pt-BFZ] and [Pt-CTZ] have been resolved. Complexes [Pt-MeIm] and [Pt-BFZ] present higher cytotoxicity than cisplatin in SW480 (colon adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian cancer) cell lines. [Pt-MeIm] shows the highest accumulation in A549 cells, in agreement with its inability to interact with serum albumin. By contrast, [Pt-CTZ] and [Pt-BFZ] interact with serum proteins, a fact that reduces their bioavailability. The strongest interaction with bovine serum albumin (BSA) is found for [Pt-BFZ], which is the least internalized inside the cells. All the complexes are able to covalently interact with DNA. The most cytotoxic complexes, [Pt-MeIm] and [Pt-BFZ] induce cellular accumulation in G0/G1 and apoptosis by a similar pathway, probably involving a reactive oxygen species (ROS) generation mechanism. [Pt-BFZ] turns out to be the most efficient complex regarding ROS generation and causes mitochondrial membrane depolarization, whereas [Pt-MeIm] induces the opposite effect, hyperpolarization of the mitochondrial membrane. On the contrary, the least cytotoxic complex, [Pt-CTZ] cannot block the cell cycle or generate ROS and the mechanism by which it induces apoptosis could be a different one.

Cyclometalated platinum(II) complexesClotrimazoleBifonazoleReactive oxygen species (ROS)AntitumoralTUMOR-CELL LINESRUTHENIUM-CLOTRIMAZOLE COMPLEXESMETAL-BASED CHEMOTHERAPYPLATINUM COMPLEXESTROPICAL DISEASESORGANORUTHENIUM COMPLEXESKETOCONAZOLE COMPLEXESANTIPARASITIC ACTIVITYCRYSTAL-STRUCTUREBINDING

Fernandez-Pampin, Natalia、Vaquero, Monica、Gil, Tania、Espino, Gustavo、Fernandez, Dario、Garcia, Begona、Busto, Natalia

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Univ Burgos

2022

10.1016/j.jinorgbio.2021.111663

Journal of Inorganic Biochemistry

Journal of Inorganic Biochemistry

ISTP
ISSN：0162-0134
年,卷(期)：2022.226
  • 5
  • 69