Thiomaltol‐Based Organometallic Complexes with 1‐Methylimidazole as Leaving Group: Synthesis, Stability, and Biological Behavior

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As eries of 16 dinuclear thiopyridone-basedo rganometallics with excellent water solubility,i ncreased stability and remarkablec ytotoxicity were synthesized and characterized. Thecomplexes of this work formed dimericspecies featuring ad ouble positive charge in polar protic solvents, accounting for their outstanding solubility in aqueous solution. Most of them displayedh igher antiproliferativea ctivity than their parental thiomaltol complex, with unexpected cytotoxicity trends depending on the employed metal center, ligand modification, and cell line. Insights into their behavior in biological systemsw ere gatheredb ym eans of amino-acid interactions tudies,c ytotoxicity tests in 3D spheroid models, laser ablation,c ellular accumulationm easurements, as well as cell cycle experiments. Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.org/10.Scheme1.Overview of synthesized thiopyridone-based piano-stool complexes. (i)methylamine, water and reflux overnight (1a), or aniline, benzylamine, or 1-naphthylamine,0.38 m HCl and microwave irradiation (t = 30 min, T = 165 8C) (1b-d); (ii)Lawesson's reagent, abs. toluene, Schlenk technique, reflux 4-16 h; (iii)[(p-cym)/(Cp*)MCl 2 ] 2 ,N aOMe, MeOHa bs.,4 08C, 1-3.5h. images of HCT-116 tumor spheroid sections incubated with organometallic ruthenium (3a,c), rhodium (5a,c), or iridium (6a,c)c omplexes at the respectiveIC 50 concentrationf or 96 h; scaleb ar 100 mm.

Section: Introductionsupporting

confidence: 90%

Synthesis, Modification, and Biological Evaluation of a Library of Novel Water‐Soluble Thiopyridone‐Based Organometallic Complexes and Their Unexpected (Biological) Behavior

Harringer

Happl

Ozenil

et al. 2020

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“…The thiomaltol ligand ( L2 ) is known to be highly cytotoxic by itself . While the activities in SW480 and CH1/PA‐1 cell lines of complex 2 are within the same range as that of the free ligand ( L2 ), the activity of 2 in the A549 cell line is significantly greater (4 to 5 times) when compared with the free ligand L2 .…”

Section: Resultsmentioning

confidence: 99%

“…The thiomaltol ligand (L2)i sk nown to be highly cytotoxic by itself. [46] While the activities in SW480 and CH1/PA-1 cell lines of complex 2 are within the same range as that of the free ligand (L2), the activity of 2 in the A549 cell line is significantly greater (4 to 5t imes) when compared with the free ligand L2.T his greatest activity of 2 in the broadly chemore-sistantA 549c ell line indicates am ode of action very different to that of known cytotoxic metal complexes. Moreover,a sf ar as we know,t his compound is the first active molybdenum complex bearing at rispyrazolylborate ligand and, the most active molybdenum complex to the best of our knowledge.…”

Section: Cytotoxic Activitymentioning

confidence: 89%

“…Molybdic acid (85 %, Alfa Aesar), triphenylphosphine oxide (98 %, Sigma Aldrich), hydrochloric acid (30–33 %, Donauchem), sodium methoxide (≈95 %, Fluka), ethyl formate (97 %, Sigma Aldrich), isopropyl methyl ketone (≥98.5 %, Sigma Aldrich), hydrazine dichloride (≥98 %, Sigma Aldrich), Potassium borohydride (98 %, Sigma Aldrich), Lawesson's reagent (99 %, Acros Organics), sodium hydroxide (≥98 %, Sigma Aldrich), hydrogen peroxide (30 %, Sigma Aldrich), thionyl chloride (≥99 %, Fluka), zink powder (≥97 %, Fisher), triphenylphosphine (99 %, Alfa Aesar), triethylamine (99 %, Sigma Aldrich), PBS (sterile filtered, Sigma Life Science), maltol ( L1 ) (99 %, Sigma–Aldrich), 2‐(2'‐pyridyl)‐1 H‐ benzimidazole ( L6 ) (97 %, Sigma Aldrich) and polyvinylpyrrolidone—average mol wt 10.000 (PVP10, Sigma Aldrich) were purchased from the respective commercial source and used as obtained. Thiomaltol ( L2 ), thioallomaltol ( L3 ), 3‐hydroxy‐2‐(4′‐chlorophenyl)chromen‐4‐one ( L4 ) and chlorohydrotris(3‐isopropyl‐1 H‐ pyrazolyl)borodioxomolybdenum(VI), Tp i Pr MoO 2 Cl, were synthesized according to literature protocols. 3‐Hydroxy‐2‐(4′‐chlorophenyl)chromen‐4‐thione ( L5 ) was synthesized by using the same procedure as for thiomaltol, described in the literature .…”

Section: Methodsmentioning

confidence: 99%

“…[52] Molybdic Aldrich) and polyvinylpyrrolidone-average mol wt 10.000 (PVP10, Sigma Aldrich) were purchased from the respective commercial source and used as obtained. Thiomaltol [46,53,54] (L2), thioallomaltol [55] (L3), 3-hydroxy-2-(4'-chlorophenyl)chromen-4-one [56] (L4)a nd chlorohydrotris(3-isopropyl-1H-pyrazolyl)borodioxomolybdenum(-VI), Tp iPr MoO 2 Cl, [57,58] were synthesized according to literature protocols. 3-Hydroxy-2-(4'-chlorophenyl)chromen-4-thione (L5)w as synthesized by using the same procedure as for thiomaltol, described in the literature.…”

Section: Methodsmentioning

confidence: 99%

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The First Anticancer Tris(pyrazolyl)borate Molybdenum(IV) Complexes: Tested in Vitro and in Vivo—A Comparison of O,O‐, S,O‐, and N,N‐Chelate Effects

Berasaluce

Cseh

Roller

et al. 2019

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The synthesis, characterization and biological activity of molybdenum(IV) complexes containing Trofimenko's scorpionato ligand, hydrotris(3‐isopropylpyrazolyl)borate (TpiPr), in addition to varying biologically active as well as other conventional ligands is described. Ligands employed include (O,O‐) (S,O‐) (N,N‐) donors that have been successfully coordinated to the molybdenum center by means of oxygen‐atom transfer (OAT) reactions from the known MoVI starting material, TpiPrMoO2Cl. The synthesized complexes were characterized by standard analytical methods and where possible by X‐ray diffraction analysis. The aqueous stability of the compounds was studied by means of UV/Vis spectroscopy and the impact of the attached ligand scaffolds on the oxidation potentials (MoIV to MoV) was studied by cyclic voltammetry. Utilizing polyvinylpyrrolidone (PVP) as a solubilizing agent, adequate aqueous solubility for biological tests was obtained. Anticancer activity tests and preliminary mode of action studies have been performed in vitro and in vivo.

Exploring the Effect of Polypyridyl Ligands on the Anticancer Activity of Phosphorescent Iridium(III) Complexes: From Proteosynthesis Inhibitors to Photodynamic Therapy Agents

Prachařová

Vigueras

Novohradský

et al. 2018

A series of five kinetically inert bis-cyclometalated Ir complexes of general formula [Ir(C^N) (N^N)][PF ] [C^N=2-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-benzo[d]imidazol-κN,C; N^N=1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3), benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn, 4), and dipyrido[3,2-a:2',3'-c]phenazine-10,11-imidazolone (dppz-izdo, 5)] were designed and synthesized to explore the effect of the degree of π conjugation of the polypyridyl ligand on their toxicity in cancer cells. We show that less-lipophilic complexes 1 and 2 exhibit the highest toxicity [sub-micromolar inhibitory concentration (IC ) values] in A2780, HeLa, and MCF-7 cancer cells, and they are markedly more efficient than clinically used platinum drugs. It is noteworthy that the investigated Ir agents display the capability to overcome acquired and inherent resistance to conventional cisplatin (in A2780cisR and MCF-7 cells, respectively). We demonstrate that the Ir complexes, unlike clinically used platinum antitumor drugs, do not kill cells through DNA-damage response. Rather, they kill cells by inhibiting protein translation by targeting preferentially the endoplasmic reticulum. Our findings also reveal that the toxic effect of the Ir complexes can be significantly potentiated by irradiation with visible light (by more than two orders of magnitude). The photopotentiation of the investigated Ir complexes can be attributed to a marked increase (≈10-30-fold) in intracellular reactive oxygen species. Collectively, these data highlight the functional diversity of antitumor metal-based drugs and the usefulness of a mechanism-based rationale for selecting candidate agents that are effective against chemoresistant tumors for further preclinical testing.