Hexanuclear and undecanuclear iron(III) carboxylates as catalyst precursors for cyclohexane oxidation

Two multinuclear complexes [Fe-6(mu(3)-O)(2)(mu(4)-O-2)L-10(OAc)(2)(H2O)(2)]center dot 2.625Et(2)O center dot 2.375H(2)O (1) and [(Fe11Cl)-Cl-III-(mu(4)-O)(3)(mu(3)-O)(5)L-16(dmf)(2.5)(H2O)(0.5)]center dot Et2O center dot 1.25dmf center dot 3.8H(2)O (2), where HL = 3,4,5-trimethoxybenzoic acid and dmf = dimethylformamide, have been prepared from trinuclear iron(III) carboxylates via their structural rearrangement in dimethylformamide or diethyl ether-dimethylformamide 9:1, respectively, and slow vapor diffusion of diethyl ether into the reaction mixture. Both compounds have been characterized by X-ray diffraction, optical, Mossbauer spectroscopy, and magnetic measurements. Complex 1 possesses a hexanuclear ferric peroxido-dioxido {Fe-6(O-2)(O)(2)}(12+) core unit, which adopts a recliner conformation, while complex 2 contains an unprecedented {Fe11O8Cl}(16+) core, in which 9 ferric ions are six-coordinate and the remaining two are five-coordinate. Another structural feature of note of the undecanuclear core is the presence of a deformed cubane entity {Fe-4(mu(3)-O)(mu(4)-O)(3)}(4+). Both complexes act as catalyst precursors for the oxidation of cyclohexane to cyclohexanol and cyclohexanone with aqueous H2O2, in the presence of pyrazinecarboxylic acid. Remarkable TONs and TOFs (the latter mainly for 1) with concomitant quite good yields have been achieved under mild conditions. Moreover, 1 exhibits remarkably high activity in an exceptionally short reaction time (45 min), being unprecedented for any metal catalyzed alkane oxidation by H2O2. The catalytic reactions proceed via Fenton type chemistry

Structure-antiproliferative activity studies on L-proline- and homoproline-4-N-pyrrolidine-3-thiosemicarbazone hybrids and their nickel(II), palladium(II) and copper(II) complexes

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l- and d‑Proline Thiosemicarbazone Conjugates: Coordination Behavior in Solution and the Effect of Copper(II) Coordination on Their Antiproliferative Activity

Two enantiomerically pure thiosemicarbazone–proline conjugates with enhanced aqueous solubility, namely, 2-hydroxy-3-methyl-(<i>S</i>)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [l-Pro-STSC or (<i>S</i>)-H₂L] and 2-hydroxy-3-methyl-(<i>R</i>)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [d-Pro-STSC or (<i>R</i>)-H₂L] have been synthesized and characterized by elemental analysis, spectroscopic methods (UV–vis and ¹H and ¹³C NMR), and electrospray ionization mass spectrometry. The metal complexation behavior of l-Pro-STSC, stoichiometry, and thermodynamic stability of iron­(II), iron­(III), copper­(II), and zinc­(II) complexes in 30% (w/w) dimethyl sulfoxide/H₂O solvent mixture have been studied by pH-potentiometric, UV–vis-spectrophotometric, circular dichroism, electron paramagnetic resonance, ¹H NMR spectroscopic, and spectrofluorimetric measurements. By the reaction of CuCl₂·2H₂O with (<i>S</i>)-H₂L and (<i>R</i>)-H₂L, respectively, the complexes [Cu­[(<i>S</i>)-H₂L]­Cl]Cl and [Cu­[(<i>R</i>)-H₂L]­Cl]Cl have been prepared and comprehensively characterized. An X-ray diffraction study of [Cu­[(<i>R</i>)-H₂L]­Cl]Cl showed the formation of a square-planar copper­(II) complex, which builds up stacks with interplanar separation of 3.3 Å. The antiproliferative activity of two chiral ligands and their corresponding copper­(II) complexes has been tested in two human cancer cell lines, namely, SW480 (colon carcinoma) and CH1 (ovarian carcinoma). The thiosemicarbazone–proline conjugates l- and d-Pro-STSC show only moderate cytotoxic potency with IC₅₀ values of 62 and 75 μM, respectively, in CH1 cells and >100 μM in SW480 cells. However, the corresponding copper­(II) complexes are 13 and 5 times more potent in CH1 cells, based on a comparison of IC₅₀ values, and in SW480 cells the increase in the antiproliferative activity is even higher. In both tested cell lines, l-Pro-STSC as well as its copper­(II) complex show slightly stronger antiproliferative activity than the compounds with a d-Pro moiety, yielding IC₅₀ values of 4.6 and 5.5 μM for [Cu­(l-Pro-STSC)­Cl]Cl in CH1 and SW480 cells, respectively

l- and d‑Proline Thiosemicarbazone Conjugates: Coordination Behavior in Solution and the Effect of Copper(II) Coordination on Their Antiproliferative Activity

Two enantiomerically pure thiosemicarbazone–proline conjugates with enhanced aqueous solubility, namely, 2-hydroxy-3-methyl-(<i>S</i>)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [l-Pro-STSC or (<i>S</i>)-H₂L] and 2-hydroxy-3-methyl-(<i>R</i>)-pyrrolidine-2-carboxylate-5-methylbenzaldehyde thiosemicarbazone [d-Pro-STSC or (<i>R</i>)-H₂L] have been synthesized and characterized by elemental analysis, spectroscopic methods (UV–vis and ¹H and ¹³C NMR), and electrospray ionization mass spectrometry. The metal complexation behavior of l-Pro-STSC, stoichiometry, and thermodynamic stability of iron­(II), iron­(III), copper­(II), and zinc­(II) complexes in 30% (w/w) dimethyl sulfoxide/H₂O solvent mixture have been studied by pH-potentiometric, UV–vis-spectrophotometric, circular dichroism, electron paramagnetic resonance, ¹H NMR spectroscopic, and spectrofluorimetric measurements. By the reaction of CuCl₂·2H₂O with (<i>S</i>)-H₂L and (<i>R</i>)-H₂L, respectively, the complexes [Cu­[(<i>S</i>)-H₂L]­Cl]Cl and [Cu­[(<i>R</i>)-H₂L]­Cl]Cl have been prepared and comprehensively characterized. An X-ray diffraction study of [Cu­[(<i>R</i>)-H₂L]­Cl]Cl showed the formation of a square-planar copper­(II) complex, which builds up stacks with interplanar separation of 3.3 Å. The antiproliferative activity of two chiral ligands and their corresponding copper­(II) complexes has been tested in two human cancer cell lines, namely, SW480 (colon carcinoma) and CH1 (ovarian carcinoma). The thiosemicarbazone–proline conjugates l- and d-Pro-STSC show only moderate cytotoxic potency with IC₅₀ values of 62 and 75 μM, respectively, in CH1 cells and >100 μM in SW480 cells. However, the corresponding copper­(II) complexes are 13 and 5 times more potent in CH1 cells, based on a comparison of IC₅₀ values, and in SW480 cells the increase in the antiproliferative activity is even higher. In both tested cell lines, l-Pro-STSC as well as its copper­(II) complex show slightly stronger antiproliferative activity than the compounds with a d-Pro moiety, yielding IC₅₀ values of 4.6 and 5.5 μM for [Cu­(l-Pro-STSC)­Cl]Cl in CH1 and SW480 cells, respectively

Copper(II) Complexes with Isomeric Morpholine-Substituted 2-Formylpyridine Thiosemicarbazone Hybrids as Potential Anticancer Drugs Inhibiting Both Ribonucleotide Reductase and Tubulin Polymerization: The Morpholine Position Matters

The development of copper(II) thiosemicarbazone complexes as potential anticancer agents, possessing dual functionality as inhibitors of R2 ribonucleotide reductase (RNR) and tubulin polymerization by binding at the colchicine site, presents a promising avenue for enhancing therapeutic effectiveness. Herein, we describe the syntheses and physicochemical characterization of four isomeric proligands H2L3–H2L6, with the methylmorpholine substituent at pertinent positions of the pyridine ring, along with their corresponding Cu(II) complexes 3–6. Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the in vitro antiproliferative activity in human uterine sarcoma MES-SA cells and the multidrug-resistant derivative MES-SA/Dx5 cells. Activity correlated strongly with quenching of the tyrosyl radical (Y•) of mouse R2 RNR protein, inhibition of RNR activity in the cancer cells, and inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity, supported by experimental results and molecular modeling calculations, are presented