A series of novel neutral NHC gold halide complexes derived from 4,5-diarylimidazoles were synthesized, characterized, and analyzed for biological effects. High growth inhibitory effects in MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon cancer cell lines depended on the presence of the C4,C5-standing aromatic rings. Methoxy groups at these rings did not change the growth inhibitory properties, while F-substituents in the ortho-position (5d) increased the activity in MCF-7 and MDA-MB 231 cells. The substituents at the nitrogen atoms and the oxidation state of the metal play a subordinate role. The most active bromo[1,3-diethyl-4,5-bis(2-fluorophenyl)-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) (5d) was distinctly more active than cisplatin. All complexes caused thioredoxin reductase (TrxR) inhibition (EC50=374-1505 nM) distinctly lower than auranofin (EC50=18.6 nM) excluding this enzyme as main target. Because of the low nuclear content, a participation of DNA interaction on the mode of action is very unlikely. The missing ER binding and the missing correlation of growth inhibition and inactivation of COX enzymes exclude these targets, too.

Beyond treating headaches: The derivatization of biologically active compounds by organometallic units modulates their pharmacological properties. In studies of antitumor‐related biochemical properties, the Co2(CO)6 derivative of aspirin 1 shows significantly modified influence on several relevant pathways, which might be based on an altered interaction with the target enzyme COX‐2.

Cationic bis[1,3-diethyl-4,5-diarylimidazol-2-ylidene]gold(I) complexes with 4-OCH3 or 4-F substituents in the aromatic rings and Br– (3a,b) or BF4 – (7a,b) counterions were synthesized, characterized, and investigated for tumor growth inhibitory properties in vitro. Analogous to auranofin, the N-heterocyclic carbenes (NHCs) were also combined with a phosphine ligand (triphenylphosphine, 4a,b) and 2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyl-1-thiolate (5a,b). The growth inhibitory effect against MCF-7, MDA-MB 231, and HT-29 cells, which is more than 10-fold higher than that of cisplatin or 5-FU, was independent of the oxidation state (Au(III), 6a,b) and the anionic counterion. Bis[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]gold(I) bromide 3b as the most cytotoxic compound reduced the growth of MCF-7 cells with IC50 = 0.10 μM (cisplatin, 1.6 μM; 5-FU, 4.7 μM). The thioredoxin reductase (TrxR), the estrogen receptor (ER), and the cyclooxygenase (COX) enzymes, which have to be considered as possible targets based on the drug design, can be excluded from being involved in the mode of action.

No abstract

Aspirin, the acetyl ester of salicylic acid, was first discovered in the late 1800s and became one of the most world-renowned drugs. Its fame is rooted in its ability to treat a wide range of symptoms such as fever, inflammation, and pain. Aspirin represents an advancement of the previously applied salicylic acid, which was obtained from myrtle leaf decoction or willow bark extract, but was found to be less active and to cause serious gastrointestinal irritation.[1] Later on, other chemical modifications of aspirin were investigated with the aim of improving its pharmacological profile. The influence of additional substituents on the phenyl ring and modification of the acetoxy and carboxy groups were studied, [2] and even the phenyl core of aspirin was replaced by the organometallic ferrocene moiety. [3] However, none of these derivatives could substitute for aspirin. We have now modified aspirin by replacing the phenyl ring with a three-dimensional and highly hydrophobic carbaborane cluster.Carbaboranes are already known in medicinal chemistry as phenyl group mimetics, and analogues of tamoxifen, [4] trimethoprim, [5] and transthyretin amyloidosis inhibitors derived from flufenamic acid and diflunisal, [6] two nonsteroidal anti-inflammatory drugs (NSAIDs), have been presented.The focal point of our research was a high-yield synthesis of asborin, the carbaborane analogue of aspirin, and the study of its pharmacological behavior. Asborin is obtained in three steps (Scheme 1) starting from ortho-dicarba-closo-dodecaborane(12) (1). In the first step one of the carbaborane carbon atoms is hydroxylated according to a protocol described by Endo and co-workers.[7] The monolithiated carbaborane is treated with trimethyl borate to give a carbaboranyl boronic ester in situ. The ester is then oxidized with peracetic acid. The second step is carboxylation of the second cluster carbon atom. Both the OH proton and the remaining carbaborane CH proton of 2 can be removed with n-butyllithium, and reaction of the resulting dilithium salt with gaseous carbon dioxide gives 1-hydroxy-1,2-dicarba-closo-dodecaborane(12)-2-carboxylic acid (3) in greater than 99 % yield after acidic workup. Compound 3, with an ortho arrangement of hydroxy and carboxy groups, is the carbaborane analogue of salicylic acid. Finally, 1-acetoxy-1,2-dicarba-closo-dodecaborane(12)-2-carboxylic acid (asborin, 4) is obtained quantitatively simply by stirring 3 in acetyl chloride. The use of acetyl chloride rather than acetic anhydride is advantageous, as it can easily be removed under reduced pressure due to its lower boiling point of 52 8C. Crystals of 4 suitable for X-ray crystallography ( Figure 1) were obtained from chloroform; hydrogen-bonded dimers are formed via the carboxy groups.Asborin, with its hydrophobic cluster framework and hydrophilic carboxy group, is remarkably amphiphilic: It dissolves in water and nonpolar organic solvents.Aspirin is one of the smallest members of the NSAID family. These compounds are structurally very diverse, but all of the...

[(μ(4)-η(2))-(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of aspirin (ASS), demonstrated high growth-inhibitory potential against various tumor cells with interference in the arachidonic acid cascade as probable mode of action. The significance of the kind of metal and cluster was verified in this structure-activity study: Co(2)(CO)(6) was respectively exchanged by a tetrameric cobalt-, trimeric ruthenium-, or trimeric ironcarbonyl cluster. Furthermore, the metal binding motif was changed from alkyne to 1,3-butadiene. Compounds were evaluated for growth inhibition, antiproliferative effects, and apoptosis induction in breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1/2 inhibitory effects at isolated isoenzymes. Additionally, the major COX metabolite prostaglandin E2 (PGE(2)) was quantified in arachidonic acid-stimulated MDA-MB 231 breast tumor cells. It was demonstrated that the metal cluster was of minor importance for effects on cellular activity if an alkyne was used as ligand. Generally, no correlation existed between growth inhibition and COX activity. Cellular growth inhibition and antiproliferative activity at higher concentrations of the most active compounds Prop-ASS-Co(4) and Prop-ASS-Ru(3) correlated well with apoptosis induction.

With the aim to design new biologically active bioinorganic drugs of aspirin, whose mode of action is based on the inhibition of the cyclooxygenase(COX) enzymes, derivatives of Zeise's salt were synthesized in this structure-activity relationship study. Surprisingly, not only these Zeise-aspirin compounds but also Zeise's salt itself showed high inhibitory potency against COX enzymes in in vitro assays. In contrast, potassium tetrachloroplatinate and cisplatin did not influence the enzyme activity at equimolar concentrations. It was demonstrated by LC-ESI tandem-mass spectrometry that Zeise's salt platinates the essential amino acids Tyr385 (active site of the enzyme) and Ser516 (will be acetylated by aspirin) of COX-1, thereby strongly impairing the function of the enzyme. This finding demonstrates for the first time that Zeise's salt is pharmacologically active and is a potent enzyme inhibitor.

Metalcarbonyl complexes with ligands derived from acetylsalicylic acid demonstrated high cytotoxic potential against various tumor cell lines and strong inhibition of the cyclooxygenase enzymes COX-1 and 2. In this study we tried to achieve comparable effects with [alkyne]silver or copper trifluoromethanesulfonate complexes which are more hydrophilic then the uncharged metalcarbonyl derivatives. All compounds were evaluated for growth inhibition against breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1 and COX-2 inhibitory effects at isolated isoenzymes. Pure ligands showed neither cytotoxic nor COX-inhibitory effects. While the silver complexes of (but-2-ynyl)-2-acetoxybenzoate (But-ASS-Ag) and (but-2-yne-1,4-diyl)-bis(2-acetoxybenzoate) (Di-ASS-But-Ag) were strong cytostatics, only the copper complex Di-ASS-But-Cu was active. At the COX enzymes the complexes were more effective than their ligands and aspirin.