Novel cis‐Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action

Abstract

One concept of improving anticancer effects of conventional platinum-based antitumor drugs consists of conjugating these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, physicochemical characterization, biological effects, and mechanisms of action of four new analogs of conventional cisplatin, namely, cis-Pt(II) complexes containing either methyl or ethyl pyrazole N-donor ligands and chlorido or iodido ligands. It is noteworthy that while chlorido complexes display activity in a variety of cancer cell lines comparable to cisplatin, iodido complexes are considerably more potent due to their enhanced hydrophobicity and consequently enhanced cellular accumulation. Moreover, all of the studied Pt(II) alkylpyrazole complexes display a higher selectivity for tumor cells and effectively overcome the acquired resistance to cisplatin. Further results focused on the mechanism of action of the studied complexes and showed that in contrast to cisplatin and several platinum-based antitumor drugs, DNA damage by the investigated Pt(II)-alkylpyrazole complexes does not play a major role in their mechanism of action. Our findings demonstrate that inhibition of the tubulin kinesin Eg5, which is essential for forming a functional mitotic spindle, plays an important role in their mechanism of antiproliferative action.

Anti-myeloma pro-apoptotic Pt(ii) diiodido complexes

“…We hypothesize that the studied anti-myeloma diiodido complexes target a different molecule(s) than DNA and trigger unique responses different from conventional platinum-based drugs. In the field of Pt iodido complexes, such unusual MoA has been reported for compounds interacting with mitotic kinesin Eg5 20 or for complexes inducing high levels of ROS and interfering with redox homeostasis of the treated cancer cells. 61…”

“…17,19,[57][58][59] On the other hand, some Pt iodido complexes did not platinate DNA to a pharmacologically significant level, usually markedly less than cisplatin. 20,26 This led us to investigate DNA platination in the model experiment with guanosine monophosphate (GMP) and in the cell-free medium with salmon sperm DNA.…”

“…17 The MoA of Pt(II) diiodido complexes likely involves interactions with biomolecules other than DNA, and the formation of protein/peptide adducts has to be con-sidered as well. [17][18][19][20] In connection to this, we hypothesized that different MoA of diiodidoplatinum(II) complexes from cisplatin could be advantageous in terms of potency against hard-to-treat tumours, such as MM, where cisplatin shows only limited activity. Thus, in this work, the substituted-imidazole-based diiodidoplatinum(II) complexes (1-7; Fig.…”

New Azido Coumarins as Potential Agents for Fluorescent Labeling and Their “Click” Chemistry Reactions for the Conjugation with closo-Dodecaborate Anion

“…Therefore, they could be of potential interest for use in BNCT for cancer. Cellular accumulation plays a fundamental role in the antiproliferative activity of low-molecular-mass compounds [ 103 , 104 ]. One of the main requirements of effective BNCT is the selective accumulation of boron-containing compounds in the tumor with a fairly high concentration (approx.…”

Metal Complexes as Promising Matrix Metalloproteinases Regulators

“…Pt(II) complexes, including cisplatin and its derivatives, are widely used as anti-cancer agents. Since the first Pt(II) complex as anti-cancer agent, cisplatin , showed side effects and toxicity on normal cells, numerous Pt(II) complexes have been developed to have lower cytotoxicity and stronger anti-tumor activity than cisplatin [ 91 , 92 , 93 , 94 , 95 ]. Moreover, as MMPs are related to the onset and progression of cancers, regulation of MMPs activity and expression by Pt(II) complexes has been suggested as a potent strategy in cancer and AD treatment.…”