Abstract
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(κ2-(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.
Highlights
Clotrimazole (CTZ) and Bifonazole (BFZ) are well known antifungal agents used in mycotic infections like athlete's foot, vulvovaginal and oropharyngeal candidiasis, among others [1,2,3]
Cell proliferation was determined by the 3-(4, 5-dimethylthiazol- 2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay (Sigma Aldrich) using the following protocol: SW480 were seeded at a density of 1 × 104, A549 cells at 5 × and A2780 at 2 × cells per well in 96 well plates
Circular dichroism (CD) spectra were recorded on a MOS-450 Biologic spectrometer (Claix, France) for samples at a Pt(II) complex/bovine serum albumin (BSA) concentrations ratio of 5 and at Pt(II) complex/Calf thymus DNA (ctDNA) concentrations ratio of 1 incubated overnight, in 2.5 mM NaCaC buffer at pH = 7.0 and T = 25 ◦C
Summary
Clotrimazole (CTZ) and Bifonazole (BFZ) are well known antifungal agents used in mycotic infections like athlete's foot, vulvovaginal and oropharyngeal candidiasis, among others [1,2,3]. Navarro et al, described the CTZ-platinum(II) complexes, cis and trans-[PtX2(CTZ)2] (X= I and Cl), that present antitumoral activity [8,28] The authors tested their activity against six tumor cell lines (prostate, pancreas, breast and colon among others) observing that both complexes showed lower cytotoxicity than cisplatin but higher than transplatin. Among the neutral cyclometalated complexes, we have synthesized a family of chiral neutral cyclometalated platinum(II) complexes with general formula [Pt(κ2-(C^N))Cl(κ1-(L))] where C^N = 2-phenyl pyridinate and L stands for 2-(2-Pyridyl)benzimidazole derived ligands functionalized with CH2-Ar (Ar = phenyl, naphtyl and pyrenyl) moieties on the imidazole fragment [34] These neutral complexes were tested as antiproliferative drugs in SW480 cancer cell lines, being the complex with the unfunctionalized 2-(2-Pyridyl)benzimidazole ligand the most cytotoxic complex in spite of that DNA was not its biological target.
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