Synthesis, Molecular Structure and Cytotoxicity of Molecular Materials Based on Water Soluble Half-Sandwich Rh(III) and Ir(III) Tetranuclear Metalla-Cycles

The neutral dinuclear complexes [(eta(5)-C5Me5)(2)Rh-2(mu-dhnq)Cl-2] (1) and [(eta(5)-C5Me5)(2)Ir-2(mu-dhnq)Cl-2] (2) (dhnqH(2) = 5,8-dihydroxy-1,4-naphthoquinone) were obtained from the reaction of (eta(5)-C5Me5)M(mu-Cl)Cl (M = Rh, Ir) with dhnqH(2) in the presence of CH3COONa. Treatment of 1 or 2 in methanol with linear ditopic ligands L (L = pyrazine, 4,4'-bipyridine or 1,2-bis(4-pyridyl) ethylene), in the presence of AgCF3SO3, affords the corresponding tetranuclear metalla-rectangles (eta(5)-C5Me5)(4)M-4(mu-dhnq)(2)(mu-L)(2) (L = pyrazine, M = Rh, 3; M = Ir, 4; L = 4,4'-bipyridine, M = Rh, 5; M = Ir, 6; L = 1,2-bis(4-pyridyl) ethylene, M = Rh, 7; M = Ir, 8). All complexes were isolated as their triflate salts and were fully characterized by infrared, H-1 and C-13 NMR spectroscopy, and some representative complexes by single-crystal X-ray structure analysis. The X-ray structures of 3, 5 and 6 confirm the formation of the tetranuclear metalla-cycles, and suggest that complexes 5 and 6 possess a cavity of sufficient size to encapsulate small guest molecules. In addition, the antiproliferative activity of the metalla-cycles 3-8 was evaluated against the human ovarian A2780 (cisplatin sensitive) and A2780cisR (cisplatin resistant) cancer cell lines and on non-tumorigenic human embryonic kidney HEK293 cells. All cationic tetranuclear metalla-rectangles were found to be highly cytotoxic, with IC50 values in the low micromolar range.

Synthesis, molecular structure, computational study and in vitro anticancer activity of dinuclear thiolato-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) complexes

Paul Joseph Dyson, Benjamin Samuel Murray

Neutral dinuclear dithiolato-bridged pentamethylcyclopentadienyl Rh(III) complexes of the type (C5Me5)(2)Rh-2(mu-SR)(2)Cl-2 (R = CH2Ph, 1; R = CH2CH2Ph, 2) and cationic dinuclear trithiolato-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) complexes of the type (C5Me5)(2)M-2(mu-SR)(3) (M = Rh, R = CH2Ph, 3; M = Rh, R = CH2CH2Ph, 5; M = Rh, R = CH2C6H4-p-tBu, 7: M = Ir, R = CH2Ph, 4; M = Ir, R = CH2CH2Ph, 6; M = Ir, R = CH2C6H4-p-tBu, 8) have been synthesized from the chloro-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) dimers (C5Me5)(2)M-2(mu-Cl)(2)Cl-2 by reaction with the corresponding thiol derivative (RSH). Complexes 3-8 were isolated as chloride salts. All complexes were obtained in good yield and were fully characterized by spectroscopic methods. The molecular structures of the neutral complexes (1 and 2) show interesting features: the two rhodium atoms are bridged by two thiolato ligands with no metal-metal bonds and the pentamethylcyclopentadienyl and chlorido ligands are oriented syn to each other, an uncommon conformation for such dinuclear complexes. These structural features were rationalized using DFT calculations. Additionally, the antiproliferative activity of the complexes was evaluated against the cancerous A2780 (cisplatin sensitive) and A2780cisR (cisplatin resistant) human ovarian cell lines and on the noncancerous HEK293 human embryonic kidney cells. All complexes were found to be active and the cationic iridium complexes 4, 6 and 8 are particularly cytotoxic, with IC50 values in the nanomolar range (IC50 < 0.1 mu M). The catalytic activity of the complexes for the oxidation of glutathione (GSH) to GSSG was evaluated by NMR spectroscopy.

Royal Society of Chemistry2013

alpha-Diimine homologues of cisplatin: synthesis, speciation in DMSO/water and cytotoxicity

Lucinda Kate Batchelor, Paul Joseph Dyson, Silvia Schoch

The Pt(ii) -diimine complexes [PtCl2{N-2-(HCNR)(2)}] (R = C6H11, 1; 4-C6H10OH, 2; 4-C6H4CH3, 3; 4-C6H4OH, 4) and [PtCl2{N-2-(CH3CNOH)(2)}] (5) were prepared in 60-81% yields from the 1:1 molar reactions of cis-[PtCl2(DMSO)(2)] with the appropriate -diimine, HCN(R) (R = C6H11, L1; 4-C6H10OH, L2; 4-C6H4Me, L3; 4-C6H4OH, L4), or dimethylglyoxime (dmgH(2)), in acetone at reflux. The reaction of cis-[PtCl2(DMSO)(2)] with two molar equivalents of dmgH(2) and NEt3 in methanol at reflux afforded the bis-dimethylglyoximato compound [Pt{N-2,N-(ON?C(CH3)C(CH3)?NOH)}(2)], [Pt(dmgH)(2)], as an insoluble material, in 97% yield. The oxalato derivative [Pt(O-2-C2O4){N-2-(HCN(C6H11))(2)}], 6, was obtained from the sequential treatment of 1 with AgNO3 and Na2C2O4, in 61% yield. Attempts to functionalize 4via esterification of the hydroxyl groups with aspirin (aspCO(2)H) led to [PtCl2{N-2-(HCN(4-C6H4OCO-asp))(2)}], 7, in an admixture with 4. All the products were characterized by elemental analysis, and IR and multinuclear NMR spectroscopy, and the molecular structures of 4THF and 5 were elucidated by single crystal X-ray diffraction. NMR spectroscopic studies in DMSO or DMSO/water/NaCl evidenced the substantial stability of 1-2 at 37 degrees C over 72 hours, whereas 3-5 released their N,N-ligand. The cytotoxic activity of 1, 2 and 6 was assessed on cisplatin sensitive and cisplatin resistant human ovarian carcinomas (A2780 and A2780cisR) and non-tumorigenic human embryonic kidney (HEK-293) cells. Compound 1 is moderately cytotoxic, whereas 2 and 6 did not display appreciable antiproliferative activity.

ROYAL SOC CHEMISTRY2018

Arene-ruthenium(II) complexes with pyrazole-based ligands bearing a pyridine moiety: Synthesis, structure, DFT calculations, and cytotoxicity

Paul Joseph Dyson, Farzaneh Fadaei Tirani, Mouna Hadiji

Two pyrazole-based ligands bearing a pyridine moiety, 3-methyl-1-(pyridin-2-yl)-5-pyrazolone (HLpy), and 3methyl-1-(pyridin-2-yl)-4-trifluoroacetyl-5-pyrazolone (HQpy,CF3), were prepared and fully characterized in the solid-state and the tautomerism of both ligands in solution was also rationalized by using Density Functional Theory. Neutral ruthenium(II) arene complexes of composition [Ru(arene)(Lpy)Cl] and [Ru(arene)(Qpy,CF3)Cl] [arene = p-cymene (cym) or hexamethylbenzene (hmb)]) were synthesized and characterized by IR, 1H, 13C, 15N and 19F NMR spectroscopy, elemental analysis and ESI mass spectrometry. The structures of complexes [Ru(hmb) (Lpy)Cl] and [Ru(hmb)(Qpy,CF3)Cl] were determined by X-ray crystallography, showing kappa 2-N,N'-coordination not only for Lpy but also for Qpy,CF3 ligand. DFT studies confirm that kappa 2O,O'-coordination, generally observed in metal complexes with 4-acyl-5-pyrazolone ligands, is not favored in this case. The cytotoxicity of ligands and complexes was evaluated against human ovarian carcinoma cells (A2780 and A2780cisR, cisplatin sensitive and cisplatin-resistant, respectively), and non-tumorous human embryonic kidney SV40 transformed (HEK293T) cells to reveal essentially equivalent activity in the cisplatin sensitive and cisplatin-resistant ovarian carcinoma cells.

ELSEVIER SCIENCE SA2021