William S. Sheldrick

Chalcogenidometalates of the heavier Group 14 and 15 elements

The review covers structural aspects of the chemistry of ternary and quaternary chalcogenidometalates of the heavier Group 14 (Ge, Sn, Pb) and 15 (As, Sb, Bi) elements, with particular emphasis being placed on polymeric anionic networks. Technological interest in the design of nanoporous materials with tailor-made properties has stimulated recent research into intermediate-temperature solid-state synthetic methods (e.g. molten flux and solventothermal techniques) for the construction of lamellar and framework anions of this type. Under these relatively mild conditions (T=100–600°C), intact molecular building blocks such as rings and chains can self-organize to a fascinating variety of polyanions, whose dimensionality and cavity/channel size can be influenced by the choice of suitable structure-directing agents such as alkali metal or alkylammonium cations. Classification of the resultant chalcogenidometalates in this review is therefore performed in terms of both the nuclearity y of the component MyEz building units (M=Group 14 or 15 element, E=S, Se or Te) and the dimensionality d of the anion network. Promising novel multifunctional materials, that combine the typical exchange and catalytic features of zeolite-like phases with the unique optoelectronic properties of Group 14/15 chalcogenides, are presented.

Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties.

Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.

Comparative in vitro evaluation of N-heterocyclic carbene gold(I) complexes of the benzimidazolylidene type.

Gold(I) complexes with a 1,3-diethylbenzimidazol-2-ylidene N-heterocyclic carbene (NHC) ligand of the type NHC-Au-L (L=-Cl, -NHC, or -PPh3) were comparatively evaluated as thioredoxin reductase (TrxR) inhibitors and antimitochondrial anticancer agents. Different effects were noted in various biochemical assays (e.g., inhibition of TrxR, cellular and mitochondrial uptake, or effects on mitochondrial membrane potential), and this was related to properties of the complexes such as bond dissociation energies and overall charge. Remarkable antiproliferative effects, a strong induction of apoptosis, and enhancement of reactive oxygen species (ROS) formation as well as other effects on tumor cell metabolism confirmed the promising potential of the complexes as novel anticancer chemotherapeutics.

Synthesis and structural characterization of η6-arene-ruthenium(II) complexes of alanine and guanine derivatives

Abstract The η 6 -arene-ruthenium(II) complexes of L-alanine (L-alaH) and L-alanine methyl ester (L-alaMe), [(η 6 C 6 H 6 )Ru(L-ala)Cl] (1) and [(η 6  C 6 H 6 )Ru(L-alaMe)Cl 2 ] (2) have been prepared and their structures established by X-ray structural analysis. The crystal lattice of 1 contains two diastereomers with opposite chiralities at the metal centre. Epimerization of these species is relatively slow in aqueous solution. Reaction of 1 with 9-ethylguanine (9Etgua) yields [(η 6 C 6 H 6 )Ru(L-ala)(9-Etgua)] Cl (3) for which two diastereomers are observed in solution and in the solid state. In contrast L-alanine methyl ester in 2 may be replaced by 9-ethylguanine leading to the formation of [(η 6 C 6 H 6 )Ru(9Etgua)Cl 2 ] (4). N7 coordination of the nucleobase is exhibited by both 3 and 4.

On the Biological Properties of Alkynyl Phosphine Gold(I) Complexes

Gold complexes have a long tradition in the treatment of the symptoms of rheumatoid arthritis. 2] Therapeutically used drugs include mainly gold(I) thiolates (e.g. aurothiomalate and auranofin), which belong to the group of diseasemodifying antirheumatic drugs (DMARDs) that are used to slow down or stop the progression of this severe and disabling rheumatic disorder. Interestingly, in vitro studies on cultured tumor cells have also indicated the considerable potential of this class of metallodrugs for tumor chemotherapy, and thioredoxin reductase is one of the enzymes identified as a critical target. Intensified research on the development of gold antitumor drugs has led to many active species such as gold(I) complexes with phosphine, thiolate, chloride, and carbene ligands as well as gold(III) derivatives. 10–12] However, a major issue in the development of new bioactive gold complexes is the preparation of complexes that show suitable stability under physiological conditions. Gold complexes with alkynyl ligands, which are widely used because of their catalytic and luminescent properties, might display reasonably stable coordinative bonds. In fact, recent initial reports on the bioactivity of alkynyl gold complexes indicate that this type of organometallic complex offers opportunities for the development of new chemotherapeutics against cancer and infectious diseases. Despite these prospectives, only three studies on the biological potential of alkynyl gold complexes have been reported so far. Here, we present the outcome of a pilot study aimed at establishing the biological profile of alkynyl phosphine gold(I) complexes. Our study shows that the critical target enzyme thioredoxin reductase can be efficiently and selectively inhibited and that cysteine and selenocysteine residues are presumably the sites of molecular interaction with the enzyme. Moreover, we quantified the cellular uptake of the complexes, established their effects on tumor cell metabolism and mitochondrial respiration, and investigated their antiangiogenic properties in zebrafish embryos. A series of six alkynyl gold(I) complexes (1–6, see Figure 1) was prepared by reacting the respective alkynes with chloro(triphenylphosphine)gold(I). The structures were confirmed by H, C, P NMR, and IR spectroscopy and

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.

Interaction of cisplatin with methionine- and histidine-containing peptides: competition between backbone binding, macrochelation and peptide cleavage

The pH- and time-dependent reaction of cis-[PtCl2(NH3)2] with the methionine- and histidine-containing peptides H-Gly-Met-OH, H-Gly-Gly-Met-OH, Ac-His-Gly-Met-OH, and Ac-His-(Ala)3-Met-OH at 313 K has been investigated by ion-pairing reverse phase HPLC and NMR spectroscopy. For equimolar solutions (c=0.8 mM, pH≈3 or 8.8), initial formation of the kinetically favored S-bound complex is followed by relatively rapid metallation of the neighboring methionine amide nitrogen NM to afford a κ2NM,S six-membered chelate. The strong trans effect of the methionine S then favors facile NH3 substitution, leading to generation of tridentate complexes such as [Pt(H-Gly-MetH–1-OH)-κ3NG,NM,S )(NH3)]+ or [Pt(H-Ac-His-GlyH–1-MetH–1-OH-κ3NG,NM,S)(NH3)]. In the case of H-Gly-Gly-Met-OH, this reaction is accompanied by loss of a second NH3 ligand in alkaline solution to generate the tetradentate κ4NG1,NG2,NM,S species. In contrast, cleavage of the backbone C(O)-N bond to the second metallated amide nitrogen after t>100 h is common to the tridentate complexes of the tri- and pentapeptides at pH<5. Although an imidazole-coordinated κ2N3H,S macrochelate is formed throughout the whole range 2.5≤pH≤10 for Ac-His-Gly-Met-OH, it slowly decays (t=10–1000 h) to the thermodynamically more stable tridentate κ3NG,NM,S complex. All major final products were separated and fully characterized by NMR and MS.

Oligomeric (η6-arene) ruthenium(II) complexes of adenine and adenosine with N6,N7 coordination

Abstract Treatment of [{RuCl2(η6-arene}2] (arene = p-cymene, C6H6) with adenine (adeH), 9-ethyladenine (9etade) and adenosine (aden) provides the complexes [{Ru(ade) (η6-p-cymene)}4] (CF3SO3)4 (2). [{Pu(9etadeH−1) (η6-p-cymene)}] (CF3SO3)3 (3) and [{Ru(adenH−1)(η6-C6H6)}3] (CF3SO3)34. The structures of complexes 2 and 3 were established by X-ray structural analysis. 2 cyrstallises in the tetragonal space group /41/a with a = b = 15.870(2), c = 35.710(7) A , Z = 4 ; 3·1.5H2O in the monoclinic space group C2/c with a = 35.985(3), b = 13.094(2), c = 28.406(3) A , Z = 8 . Common to 2–4 is the participation of N6 and N7 in a five-membered chelate ring, which leads to a characteristic upfield shift in the 1H NMR signal of the pyrimidine proton H2. The tetrameric complex 2 exhibits the μ-1κN9:2κ2N6,N7 coordination mode for the bridging adeninate ligands, the trimeric complexes 3 and 4 the μ-1κN1:2κ2N6,N7 mode for the 9-substituted derivatives.

Synthesis and structural characterization of η6-arene-ruthenium(II) complexes of α-amino acids with coordinating side chains

Abstract η6-Areneruthenium(II) complexes of the amino acids l-penicillamine (l-penH), l-histidine (l-hisH), l-histidine methyl ester (l-hisMe) and the peptide triglycine (glyglyglyH) have been prepared by reaction of these amino acids with [(η6-C6H6)RuCl2]2. Crystal structure analyses are reported for [(η6-C6H6)Ru(l-pen)]2Cl2 (1), [(η6-C6H6)Ru(l-hisMe)Cl]Cl (3) and [(η6-C6H6)Ru(glyglygly)Cl] (4). The amino acidate ligands are tridentate in 1, with the deprotonated sulphur atoms adopting a bridging position between two ruthenium atoms, leading to the formation of a four-membered RuSRuS-ring. Bidentate N(ammine), N(imidazole) and N(ammine), N(peptide) binding, respectively, are exhibited by the complexes 3 and 4. The factors influencing the observed metal binding sites and chiralities are discussed.

(η5-Pentamethylcyclopentadienyl)iridium(III) complexes of purine nucleobases and nucleotides: a comparison with (η6-arene)ruthenium(II) and (η5-pentamethylcyclopentadienyl)rhodium(III) species

Abstract Treatment of [(η5-C5Me5)Ir(H2O)3](CF3SO3)2 with adenine (AH) and 9-ethyladenine (9-EtA) affords the respective tetra- and trinuclear complexes [{(η5-C5Me5)Ir(A)}4](CF3SO3)4 (1) and [{(η5-C5Me5)Ir(9-EtAH−1)}3](CF3SO3)3 (2), whose structures were established by X-ray analysis. The former compound exhibits a μ-1κN9:2κ2N6,N7 coordination mode for the bridging adeninate ligands, the latter a μ-1κN1:2κ2N6,N7 binding pattern, associated with a wide IrN7C8 angle of 149° and substantial respectively upfield (δ 7.65) and downfield (δ 8.82) shifts for the purine ring protons H2 and H8. Exclusive formation of analogous diastereomeric trimers is likewise observed in the pH* range 3.5–9.0 for equimolar equilibrium systems of [(η5-C5Me5)Ir(H2O)3]2+ with 5′-AMP2− and 5′-ATP4−. Reaction of this organometallic fragment with guanine (GH) and hypoxanthine (HxH) also provides tetramers [{(η5-C5Me5)Ir(B)(H2O)}4](CF3SO3)4 3 (B=G) and 4 (B=Hx) in which, however, O6 only participates in outer-sphere coordination through O6⋯H–O interactions to the water ligand. The μ-N7,N9 coordination mode in 3 and the analogous complex [{(η6-C6H6)Ru(Hx)(H2O)}4](CF3SO3)4 (5) was confirmed by X-ray analysis. Two cyclic (presumably trimeric) oligomers with respectively μ-1κN9:2κ2O6,N7 and μ-1κN1:2κ2N7,O(H2O) binding patterns are present at an approximately 1:1 ratio in weakly acid equimolar equilibrium systems of [(η5-C5Me5)Ir(H2O)3]2+ with 5′-IMP2− and 5′-ITP4−. Phosphate coordination is absent for this fragment in the presence of purine nucleoside 5′-triphosphates, in striking contrast to (η6-C6H6)Ru(II) and (η5-C5Me5)Rh(III), whose pH-dependent reaction behaviour is reported for comparison purposes.