Kerstin Bensdorf

NHC gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents.

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.

Modulation of the Biological Properties of Aspirin by Formation of a Bioorganometallic Derivative

Despite recent advances in modern tumor therapy the development of effective drugs remain a challenge for medicinal chemists. The demand for innovative agents triggers interest in novel chemical strategies and new concepts for modern drug design. The vast majority of drugs used to date are purely “organic” compounds. However, stimulated by the tremendous success of the inorganic compound cisplatin in modern tumor therapy, interest in the development of other metal complexes has been rapidly growing. Bioorganometallic chemistry is a novel emerging field in medicinal chemistry, which aims at probing the biological (and therapeutic) potential of organometallic compounds. As a result of their different coordination geometries, chemical properties, and reactivities, metal complexes offer a wide spectrum of functional groups more or less unexplored in modern drug design and development. The hexacarbonyldicobalt moiety Co2(CO)6 bound to an alkyne, is one such functional group, for which promising results on medical applications have been reported. For example, Co2(CO)6 derivatives of antiepileptic drugs (e.g. carbamazepine) were used as diagnostic tools in the so-called carbonyl metallo immuno assay (CMIA), and complexes with fructopyranose, nucleoside, and neuropeptide ligands displayed interesting bioactivities. We have recently reported on alkyne hexacarbonyldicobalt species with promising antiproliferative properties. Interestingly, the cell growth inhibitory activity of the complexes depended strongly on the chemical structure of the alkyne ligand. Weakly active and inactive derivatives showed that the cobalt cluster does not cause general (unspecific) cytotoxic effects. In further studies the Co2(CO)6 complex of the aspirin (o-acetylsalicylic acid, ASS) derivative prop-2-ynyl-2-acetoxybenzoate (Co-ASS) emerged as a lead compound for this class of antiproliferative agents.

Synthesis and biological studies of silver N-heterocyclic carbene complexes derived from 4,5-diarylimidazole.

A novel class of silver N-heterocyclic carbene complexes (5a-f) were synthesized in high yield by reacting silver(I) oxide with 4,5-diarylimidazolium halides (4a-f). The complexes were characterized using NMR and IR spectroscopy. The structure was confirmed on the example of bromo[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]silver(I) (5c) by crystal structure analysis. The X-ray structure indicated a three-dimensional coordination polymer with a repeating unit consisting of a C(carben)-Ag(2)-Br(2)-C(carben) cluster. Pharmacological investigations revealed that all silver complexes possessed growth inhibitory effects against breast cancer (MCF-7 and MDA-MB-231) as well as colon carcinoma (HT-29) cells. The most active compound 5c was slightly less active against MCF-7 cells, more active against MDA-MB-231 cells and comparable active as cisplatin against HT-29 cells. Further pharmacological investigations were performed with selected compounds on estrogen receptor (ER) binding, DNA intercalation, cyclooxygenase (COX) inhibition and antibacterial activity. The complexes were only marginally active at the DNA, ER and the COX enzymes, so these targets can be excluded to be involved in the mode of action. However, the growth of bacteria was significantly inhibited by 5c and 5f and opens a new application of this complex type.

Asborin: The Carbaborane Analogue of Aspirin

Asborin, the carbaborane analogue of aspirin, was obtained by a high‐yield synthetic procedure and proved to be an active cyclooxygenase (COX) inhibitor (H: white, B: beige, C: gray, O: blue).

Synthesis and Biological Activities of Transition Metal Complexes Based on Acetylsalicylic Acid as Neo-Anticancer Agents

[(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.

Investigations on cytotoxicity and anti-inflammatory potency of licofelone derivatives

A series of C5-substituted licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid) derivatives were developed by a parallel synthesis approach and investigated for cytotoxicity against MCF-7 and MDA-MB-231 cells as well as for anti-inflammatory potency in vitro and in vivo. Dependent on the C5-substituent, the compounds showed high selectivity for MCF-7 cells. Especially 2-oxoethyl benzoate derivatives were inactive at the MDA-MB-231 cell line and as active as 5-FU at MCF-7 cells. C5-acetyl (8a), -2-oxoethyl formiate (8e), -2-oxoethyl acetate (8f) and -2-oxoethyl propionate (8g) derivatives showed growth inhibition at both cell lines, comparable with cisplatin. Modifications significantly reduced the inhibitory potency at COX-1 and COX-2 in vitro and in the xylene-induced ear swelling assay in mice. Only compound 8a was equipotent to licofelone, ibuprofen and celecoxibe in vivo.

[Cyclopentadienyl]metalcarbonyl complexes of acetylsalicylic acid as neo-anticancer agents.

[(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of the nonsteroidal anti-inflammatory drug aspirin(®) (ASS), demonstrated high cytotoxic potential against various tumor cells. The [acetylene]Co(2)(CO)(6) cluster strongly increased the biological effects compared to aspirin(®). In this study we evaluated the use of [cyclopentadienyl]metalcarbonyl as cytotoxic moiety with a broader series of metals: molybdenum, manganese, cobalt and rhodium. All compounds were tested for cytotoxicity against breast (MCF-7, MDA-MB-231) and colon cancer (HT-29) cell lines. Their COX-1 and COX-2 inhibitory effects were evaluated at isolated isoenzymes. Additionally, the influence on the level of the major COX metabolite prostaglandin E(2) (PGE(2)) was quantified in MDA-MB-231 breast cancer cells. Whereas the pure ligands or ASS did not show any cytotoxic effect, all metal complexes inhibited the tumor cell growth. The inhibitory effects at COX-1 and COX-2 enzymes were low. Only the Prop-Cp-ASS-Rh complex (10 μM) caused an important inhibition of COX-1 by 60% and COX-2 by 30%. ASS showed at the same concentration only a marginal repression of COX-1 activity (30%) and no effect on COX-2.

Synthesis, Characterisation and Biological Evaluation of Copper and Silver Complexes based on Acetylsalicylic Acid

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.

Synthesis and Biological Activities of 2-Amino-thiazole-5-carboxylic Acid Phenylamide Derivatives

In an attempt to develop potent and selective anti‐tumor drugs, a series of novel 2‐amino‐thiazole‐5‐carboxylic acid phenylamide derivatives were designed based on the structure of dasatinib. All compounds were synthesized by a systematic combinatorial chemical approach. Biological evaluation revealed that N‐(2‐chloro‐6‐methylphenyl)‐2‐(2‐(4‐methylpiperazin‐1‐yl)acetamido)thiazole‐5‐carboxamide (6d) exhibited high antiproliferative potency on human K563 leukemia cells comparable to dasatinib. Against mammary and colon carcinoma cells 6d was either inactive (MDA‐MB 231) or distinctly less active (MCF‐7 and HT‐29: IC50 = 20.2 and 21.6 µM, respectively). Dasatinib showed at each cell line IC50 < 1 µM. The results of this structure activity relationship study clearly documented that the pyrimidin‐4‐ylamino core of dasatinib is responsible for the anti‐tumor activity against non‐leukemia cell lines.

Licofelone–Nitric Oxide Donors as Anticancer Agents

Five licofelone ([2,2‐dimethyl‐6‐(4‐chlorophenyl)‐7‐phenyl‐2,3‐dihydro‐1H‐pyrrolizin‐5‐yl]acetic acid) nitric oxide donor conjugates were developed by a parallel synthesis approach. The biological screening revealed that compounds with a propyl (6b), butyl (6c), or octyl (6d) chain between licofelone and the nitric oxide donor exhibited high antiproliferative potency at MCF‐7 and MDA‐MB–231 breast cancer as well as at HT‐29 colon cancer cells. Moreover, 6b–d possessed at least 2‐fold higher cytotoxicity at MDA‐MB‐231 cells than the parent compound licofelone although they showed less inhibitory activity at COX‐1 and COX‐2. A correlation between COX inhibition and growth inhibitory properties is not visible. However, the high levels of nitric oxide production of the compounds may result in their high cytotoxic activity.