Synthesis, characterisation and in vitro antitumour potential of novel Pt(II) estrogen linked complexes

The Cu(I) alkyne azide click reaction of 17α-ethynylestradiol and di-tert-butyl (2-azidopropane-1,3-diyl)dicarbamate afforded the novel 1,4 disubstituted 1,2,3 triazole and estrogen-based ligand 2-(4-(estradiol)-1H-1,2,3-triazol-1-yl)propane-1,3-diamine, EDiolDap. Reaction of EDiolDap with Pt(II) DMSO precursors, cis-[PtCl2(DMSO)2] and cis-[Pt(CBDCA)(DMSO)2] gave the corresponding Pt(II) estrogen linked complexes [PtCl2(EDiolDap)] and [Pt(CBDCA)(EDiolDap)] respectively in good yield. Both Pt(II) estrogen linked complexes exhibited superior activity as compared to cisplatin and carboplatin in 2D culture and exhibited ca. 30 fold higher activity, in terms of IC50 values, against ER+ cancer cells (cervical, breast and ovarian) as compared to the reference ER− colon cancer line. [PtCl2(EDiolDap)] and [Pt(CBDCA)(EDiolDap)] retained their anti-tumour activity in an ovarian 3D spheroid culture model and reduced the viability of ovarian cancer cell spheroids ca. 9-fold and 5-fold better, respectively, as compared to cisplatin

Novel Mixed-Ligand Copper(I) Complexes: Role of Diimine Ligands on Cytotoxicity and Genotoxicity

Novel tetrahedral copper­(I) mixed-ligand complexes of the type [Cu­(X)­(N^∩N)­(PCN)], <b>3</b>–<b>10</b>, where X = Cl or Br, N^∩N = 2,2′-bipyridine (bipy), 1,10-phenanthroline (phen), 5,6-dimethyl-1,10-phenanthroline (dmp), and dipyrido-[3,2-<i>d</i>:2′,3′-<i>f</i>]-quinoxaline (dpq), and PCN = tris-(2-cyanoethyl)­phosphine, have been synthetized and characterized by NMR, ESI-MS, and X-ray diffraction on two representative examples, [CuCl­(phen)­(PCN)]·DMF (<b>5</b>·DMF) and [CuBr­(dpq)­(PCN)]·2DMF (<b>10</b>·2DMF). Cu­(I) complexes were evaluated for their in vitro antitumor properties against a panel of human cancer cell lines, including cisplatin- and multidrug-resistant sublines. The most effective complex, [CuCl­(dpq)­(PCN)] (<b>9</b>), exhibited nanomolar cytotoxicity toward both sensitive and resistant cancer cells, but it significantly inhibited the growth of cultured normal cells. In vitro DNA assays and single cell gel electrophoresis revealed that <b>9</b> induced DNA fragmentation resulting in cell apoptosis. In parallel, fluorescence in situ hybridization (FISH) micronucleus assay attested high levels of genotoxicity following treatment of peripheral blood lymphocytes with complex <b>9</b>, suggesting that the potential risk posed by diimine metal complexes should be carefully reconsidered

Novel Mixed-Ligand Copper(I) Complexes: Role of Diimine Ligands on Cytotoxicity and Genotoxicity

Novel tetrahedral copper­(I) mixed-ligand complexes of the type [Cu­(X)­(N^∩N)­(PCN)], <b>3</b>–<b>10</b>, where X = Cl or Br, N^∩N = 2,2′-bipyridine (bipy), 1,10-phenanthroline (phen), 5,6-dimethyl-1,10-phenanthroline (dmp), and dipyrido-[3,2-<i>d</i>:2′,3′-<i>f</i>]-quinoxaline (dpq), and PCN = tris-(2-cyanoethyl)­phosphine, have been synthetized and characterized by NMR, ESI-MS, and X-ray diffraction on two representative examples, [CuCl­(phen)­(PCN)]·DMF (<b>5</b>·DMF) and [CuBr­(dpq)­(PCN)]·2DMF (<b>10</b>·2DMF). Cu­(I) complexes were evaluated for their in vitro antitumor properties against a panel of human cancer cell lines, including cisplatin- and multidrug-resistant sublines. The most effective complex, [CuCl­(dpq)­(PCN)] (<b>9</b>), exhibited nanomolar cytotoxicity toward both sensitive and resistant cancer cells, but it significantly inhibited the growth of cultured normal cells. In vitro DNA assays and single cell gel electrophoresis revealed that <b>9</b> induced DNA fragmentation resulting in cell apoptosis. In parallel, fluorescence in situ hybridization (FISH) micronucleus assay attested high levels of genotoxicity following treatment of peripheral blood lymphocytes with complex <b>9</b>, suggesting that the potential risk posed by diimine metal complexes should be carefully reconsidered

<i>In Vitro</i> and <i>in Vivo</i> Anticancer Activity of Copper(I) Complexes with Homoscorpionate Tridentate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands

Tetrahedral copper­(I) TpCuP complexes <b>1</b>–<b>15</b>, where Tp is a <i><i>N,N</i>,N</i>-tris­(azolyl)­borate and P is a tertiary phosphine, have been synthesized and characterized by means of NMR, ESI-MS, and XAS-EXAFS, and X-ray diffraction analyses on the representative complexes <b>1</b> and <b>10</b>, respectively. All copper­(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB­(pz)₃]­Cu­(PCN), <b>1</b>, and [HB­(pz)₃]­Cu­(PTA), <b>2</b>, showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity associated with endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation. No biochemical hallmarks of apoptosis were detected, and morphology studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex <b>1</b> was validated in the murine Lewis Lung Carcinoma (LLC) model

Synthesis and Biological Activity of Ester- and Amide-Functionalized Imidazolium Salts and Related Water-Soluble Coinage Metal N‑Heterocyclic Carbene Complexes

<i>N</i>-Heterocyclic carbene (NHC) ligand precursors, namely, HIm^ACl [1,3-bis­(2-ethoxy-2-oxoethyl)-1<i>H</i>-imidazol-3-ium chloride] and HIm^BCl {1,3-bis­[2-(diethylamino)-2-oxoethyl]-1<i>H</i>-imidazol-3-ium chloride}, functionalized with hydrophilic groups on the imidazole rings have been synthesized and were used in the synthesis of corresponding carbene complexes of silver­(I) and copper­(I), {[Im^A]­AgCl}, {[Im^A]­CuCl}, and {[Im^B]₂Ag}­Cl. Related Au^INHC complexes {[Im^A]­AuCl} and {[Im^B]­AuCl} have been obtained by transmetalation using the silver carbene precursor. These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. HIm^BCl and the gold­(I) complexes {[Im^A]­AuCl} and {[Im^B]­AuCl} were also characterized by X-ray crystallography. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin-sensitive and -resistant cells. The silver­(I) complex {[Im^B]₂Ag}Cl was found to be the most active, with IC₅₀ values about 2-fold lower than those achieved with cisplatin in C13*-resistant cells. Growth-inhibitory effects evaluated in human nontransformed cells revealed a preferential cytotoxicity of {[Im^B]₂Ag}Cl versus neoplastic cells. Gold­(I) and silver­(I) carbene complexes were also evaluated for their ability to in vitro inhibit the enzyme thioredoxin reductase (TrxR). The results of this investigation showing that TrxR appeared markedly inhibited by both gold­(I) and silver­(I) derivatives at nanomolar concentrations clearly point out this selenoenzyme as a protein target for silver­(I) in addition to gold­(I) complexes

Novel Imino Thioether Complexes of Platinum(II): Synthesis, Structural Investigation, and Biological Activity

The reactions of the nitrile complexes <i>cis</i>- and <i>trans</i>-[PtCl₂(NCR)₂] (R = Me, Et, CH₂Ph, Ph) with an excess of ethanethiol, EtSH, in the presence of a catalytic amount of <i>n</i>-BuLi in tetrahydrofuran (THF), afforded in good yield the bis-imino thioether derivatives <i>cis</i>-[PtCl₂{<i>E</i>-N­(H)C­(SEt)­R}₂] (R = Me (<b>1</b>), Et (<b>2</b>), CH₂Ph (<b>3</b>), Ph (<b>4</b>)) and <i>trans</i>-[PtCl₂{<i>E</i>-N­(H)C­(SEt)­R}₂] (R = Me (<b>5</b>), Et (<b>6</b>), CH₂Ph (<b>7</b>), Ph (<b>8</b>)). The imino thioether ligands assumed the <i>E</i> configuration corresponding to a <i>cis</i> addition of the thiol to the nitrile triple bond. The spectroscopic properties of these complexes have been reported along with the molecular structures of <b>1</b>, <b>2</b>, and <b>7</b> as established by X-ray crystallography which indicated that these compounds exhibit square-planar coordination geometry around the platinum center. Four N–H···Cl intermolecular contacts (N–H···Cl ca. 2.5–2.7 Å) between each chlorine atom and the N–H proton of the imino thioether ligand gave rise to “dimers” Pt₂Cl₄L₄ (L = imino thioether) formed by two PtCl₂L₂ units. The cytotoxic properties of these new platinum­(II) complexes were evaluated against various human cancer cell lines. Among all derivatives, <i>trans</i>-[PtCl₂{<i>E</i>-N­(H)C­(SEt)­CH₂Ph}₂] showed the greatest in vitro cytotoxic activity being able to decrease cancer cell viability roughly 3-fold more effectively than cisplatin

Peroxidase activity.

*<p>The amount of t-BHP reduced was calculated from the amount NADPH oxidized after 6 min. The mixture contained 50 µM GSH, 0.2 mM NADPH, 2 mM EDTA, 0.1 mg/mL BSA, and 6 µg/mL yGR and 1 µM Grx in 100 mM Tris-HCl. Selenite and SAM were added to a final concentration of 5 µM and 4 mM respectively.</p

Effect of selenium compounds on superoxide production.

<p>H157 cells were stained with hydroethidine and treated for 5 h with selenite (5 µM) +/− SAM (500 µM), and MSA (5 µM) before detection of accumulated superoxide produced by FACS analysis, as described under materials and methods.</p

TEM images at 20 nm zoom of: a) glc-IONP-treated cells; b) PVP-IONP-treated cells.

<p>TEM images at 20 nm zoom of: a) glc-IONP-treated cells; b) PVP-IONP-treated cells.</p

High Resolution TEM micrograph, magnification 600000x (A) and FFT image performed on a particle of glc-IONP (B).

<p>High Resolution TEM micrograph, magnification 600000x (A) and FFT image performed on a particle of glc-IONP (B).</p