Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt( cis -1,3-diaminocycloalkane)Cl
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ORIGINAL PAPER
Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis‑1,3‑diaminocycloalkane)Cl2] analogs James D. Hoeschele1 · Jana Kasparkova2 · Hana Kostrhunova2 · Olga Novakova2 · Jitka Pracharova2 · Paul Pineau1 · Viktor Brabec2 Received: 25 June 2020 / Accepted: 10 August 2020 © Society for Biological Inorganic Chemistry (SBIC) 2020
Abstract The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(cis-1,4-DACH)Cl2], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes wherein the cis-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(cis-1,3-DACH)Cl2] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(cis-1,3-diaminocycloalkane) Cl2] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(cis-1,3-diaminocycloalkane) Cl2] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(cis1,3-DACH)Cl2] originates from its highest hydrophobicity and most efficient cellular uptake.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00775-020-01809-9) contains supplementary material, which is available to authorized users. * Viktor Brabec [email protected] 1
Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, USA
Institute of Biophysics, Czech Academy of Sciences, Kralovopolska 135, 61265 Brno, Czech Republic
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Vol.:(0123456789)
JBIC Journal of Biological Inorganic Chemistry
Graphic abstract
Keywords Antitumor · Oxaliplatin · Pt(1,n-diaminocycloalkane) moiety · DNA · Glutathione · Cellular uptake
Introduction Antitumor platinum(II) complexes have played a dominant role in the chemotherapeutic treatment of solid cancerous t
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