Fabian Mohr

Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation as Potential Anticancer Agents

Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.

Fluorescent silver(I) and gold(I)-N-heterocyclic carbene complexes with cytotoxic properties

Silver(I) and gold(I)-N-heterocyclic carbene (NHC) complexes bearing a fluorescent anthracenyl ligand were examined for cytotoxicity in normal and tumor cells. The silver(I) complex exhibits greater cytotoxicity in tumor cells compared with normal cells. Notably, in cell extracts, this complex determines a more pronounced inhibition of thioredoxin reductase (TrxR), but it is ineffective towards glutathione reductase (GR). Both gold and silver complexes lead to oxidation of the thioredoxin system, the silver(I) derivative being particularly effective. In addition, the dimerization of peroxiredoxin 3 (Prx3) was also observed, demonstrating the ability of these compounds to reach the mitochondrial target. The fluorescence microscopy visualization of the subcellular distribution of the complexes shows a larger diffusion of these molecules in tumor cells with respect to normal cells.

Synthesis, Characterization, and in Vitro Cytotoxicity of Some Gold(I) and Trans Platinum(II) Thionate Complexes Containing Water-Soluble PTA and DAPTA Ligands. X-ray Crystal Structures of [Au(SC4H3N2)(PTA)], trans-[Pt(SC4H3N2)2(PTA)2], trans-[Pt(SC5H4N)2(PTA)2], and trans-[Pt(SC5H4N)2(DAPTA)2]

A series of gold(I) and platinum(II) complexes of the type [Au(SR)(P)] and trans-[Pt(SR) 2(P) 2] [SR = 2-thiopyridine (SPy), 2-thiopyrimidine (SPyrim); P = 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA)] were prepared and characterized, and their in vitro cytotoxicities against a panel of seven human cancer cell lines were evaluated. The highly water soluble gold(I) complexes [Au(SR)(P)] [P = PTA and SR = SPy ( 1), SPyrim ( 2); P = DAPTA and SR = SPy ( 3), SPyrim ( 4)] showed low cytotoxicity, while the platinum(II) complexes trans-[Pt(SR) 2(P) 2] [P = PTA and SR = SPyrim ( 5), SPy ( 6); P = DAPTA and SR = SPyrim ( 7), SPy ( 8)] demonstrated potent cytotoxicity for ovarian, colon, renal, and melanoma cancer cell lines on the basis of a comparison with ID 50 values for some established cytotoxic drugs. Single crystals of 2, 5, 6, and 8 suitable for X-ray structural characterization were obtained, and the study revealed the trans configuration for 5, 6, and 8 in their solid states.

TrxR inhibition and antiproliferative activities of structurally diverse gold N-heterocyclic carbene complexes

Gold compounds with N-heterocyclic carbene (NHC) ligands have been widely described as potent thioredoxin reductase (TrxR) inhibitors and effective anticancer agents. However, despite these promising aspects structure–activity-relationship (SAR) studies still remain limited. In this study a structurally diverse library of gold(I) and gold(III) NHC complexes was investigated for inhibitory capacity against TrxR and for antiproliferative activity in HT-29 human colon adenocarcinoma cells with the aim of identifying a valid SAR. Overall results indicated that the bioactivity, carried by the gold center, is intimately linked to the chemical properties of the residues at the NHC scaffold as well as other ligands coordinated to the gold atom. Although a direct correlation between IC50 values for cytotoxicity and enzyme inhibition could not be established, the inhibition of TrxR represents an important parameter to achieve a good cytotoxic activity.

Synthesis and biological studies of some gold(I) complexes containing functionalised alkynes

The propargyl ethers 7-chloro-(4-propargyloxy)quinoline, 1-propargyloxynaphthalene and 2-propargyloxybenzophenone react with [AuCl(PPh(3))] in the presence of KOH to give the gold(I) alkynyl complexes [Au(C[triple bond]COCH(2)Ar)(PPh(3))] in good yields. The compounds were fully characterised by spectroscopic methods and were subsequently examined for their biological activity against four tumour cell lines as well as their activity against Plasmodium falciparum, the parasite responsible for malaria. The compounds show antiproliferative effects in human cancer cells with IC(50) values ranging from 0.4-12 microM.

trans-Thionate Derivatives of Pt(II) and Pd(II) with Water-Soluble Phosphane PTA and DAPTA Ligands: Antiproliferative Activity against Human Ovarian Cancer Cell Lines

A series of PTA and DAPTA platinum(II) and palladium(II) thionate complexes of the type trans-[M(SN)2P2] were prepared from the reaction of cis-[MCl2P2] [M = Pt, Pd; P = PTA (1,3,5-triaza-7-phosphaadamantane), DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)] with the in situ generated sodium salts of the heterocyclic thiones S-m-methylpyrimidine-2-thione, S-4,6-dimethylpyrimidine-2-thione, S-4,6-dihydroxypyrimidine-2-thione, benzothiazole-2-thione, benzoxazole-2-thione, S-1,3,4,-thiadiazole-2-thione, S-4,5-H-thiazolan-2-thione, and S-pyrimidine-4(1H)-one-2-thione. The X-ray structures of six of the compounds confirm the trans disposition and, only in the case of [Pd2Cl2(S-pyrimidine-4(1H)-one-2-thionate)2(PTA)2], a dinuclear structure with a Pd-Pd distance of 3.0265(14)Å was observed. In vitro cytotoxicities against human ovarian cancer cell lines A2780 and A2780cisR were evaluated for ten complexes showing a high inhibition of cellular growth with a comparable inhibitory potency (IC50) against A2780 cells to that of cisplatin. Notably, the compounds also show significant (up to 7-fold higher) activity in cisplatin-resistant A2780cisR cell lines.

Macrocyclic gold(I) complexes and [2]catenanes containing carbonyl functionalized diacetylide ligands

Abstract The carbonyl derivatized bis(alkyne) OC(4-C 6 H 4 OCH 2 CCH) 2 was converted into the imine derivatives RNC(4-C 6 H 4 OCH 2 CCH) 2 [R=OH, NHC(O)NH 2 , NHC 6 H 3 -2,4-(NO 2 ) 2 ] and into the 4-bromomethyl-1,3-dioxolane derivative BrCH 2 C 2 H 3 O 2 C(4-C 6 H 4 OCH 2 CCH) 2 . The alkyne units in these compounds react with [AuCl(SMe 2 )] in the presence of base to form the corresponding digold(I) diacetylide complexes, that exist as insoluble oligomers or polymers. They reacted with the diphosphines Ph 2 PZPPh 2 [Z=CC, trans -HCCH and (CH 2 ) n , n =3–5] to give macrocyclic gold(I) complexes of the type [Au 2 (μ-LL)(μ-PP)], where LL is the diacetylide and PP the diphosphine ligand. The ability of these macrocyclic complexes to self-assemble to [2]catenanes has been studied. The ketone and imine derivatives do not form [2]catenanes because the orientation of the aryl groups is unfavorable, but the 1,3-dioxolane derivatives may catenate if the ring size is optimum.

Synthesis, structures and in vitro cytotoxicity of some platinum(II) complexes containing thiocarbamate esters.

The thiocarbamate esters 4-RC6H4NHC(S)OMe (R = H, Cl, OMe, NO2, Me) react with cis-[PtCl2(PTA)2] (PTA=1,3,5-triaza-7-phosphaadamantane) in the presence of base to afford the platinum(II) complexes trans-[Pt{SC(OMe)NC6H4R}2(PTA)2] (R=H, Cl, OMe, NO2, Me) in high yields. The complexes were fully characterised spectroscopically and, in case of the NO2 derivate, by X-ray crystallography. Cytotoxicity of these complexes was studied in vitro in four human cancer cell lines (CH1, HT29, A549, SK-OV-3) using the MTT assay. The results show that the Cl substituted derivate is the most potent of these compounds in vitro. Moreover, this derivative is capable of partially circumventing primary cisplatin resistance in ovarian and colon carcinoma cells.

The chemistry of gold-fluoro compounds: A continuing challenge for gold chemists

This article gives a brief overview of the chemistry of gold-fluoro compounds known to date. The synthesis, structures, reactivity and computational results of gold fluorides are reviewed, discussed according to the gold oxidation state. The literature up to (and including) 2003 has been covered.

The importance of C–H⋯N, C–H⋯π and π⋯π interactions in the crystal packing of the isomeric N1,N4-bis((pyridine-n-yl)methylene)-cyclohexane-1,4-diamines, n = 2, 3 and 4

The molecular structures of the isomeric N1,N4-bis((pyridine-n-yl)methylene)-cyclohexane-1,4-diamines, where n = 2 (1), 3 (2) and 4 (3), show the same effective conformation, in particular between the n-pyridine rings and the bridging cyclohexane rings. Theoretical structures of 1–3 are more symmetric and confirm that the pyridine residues are orthogonal to the plane through the four methylene groups of the bridging cyclohexyl groups. Crystal packing in 1–3 is dominated by C–H⋯Npyridine interactions. In 1, these interactions lead to linear chains and, along with π⋯π contacts, give rise to a layer structure. In 2, the C–H⋯Npyridine interactions extend in three dimensions and are complemented by C–H⋯N imine and C–H⋯π contacts. Finally, in 3, the C–H⋯Npyridine interactions lead to layers that are connected by C–H⋯π interactions to give a 3D network. It appears that in the structures of 1–3, the relative disposition of the pyridine and imine groups allows for the participation of the former in intermolecular interactions owing to their accessibility compared with the latter.