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Tumor cell chemoresistance is a major challenge in cancer therapeutics. Major select metal-based drugs are potent anticancer mediators yet they exhibit adverse sideeffects and are efficient against limited types of malignancies. A need, therefore, arises for novel metallodrugs with improved efficacy and decreased toxicity. Enhancement of antitumor drugs based on anticancer metals is currently a very active research field, with considerable efforts having been made toward elucidating the mechanisms of immune action of complex metalloforms and optimizing their immunoregulatory bioactivity through appropriate synthetic structural modification(s) and encapsulation in suitable nanocarriers, thereby enhancing their selectivity, specificity, stability, and bioactivity. In that respect, comprehending the molecular factors involved in drug resistance and immune response may help us develop new approaches toward more promising chemotherapies, reducing the rate of relapse and overcoming chemoresistance. In this review, a) molecular immunerelated mechanisms in the tumor microenvironment, responsible for lower drug sensitivity and tumor relapse, along with b) strategies for reversing drug resistance and targeting immunosuppressive tumor networks, while concurrently optimizing the design of complex metalloforms bearing anti-tumor activity, are discussed in an effort to identify and overcome chemoresistance mechanisms for effective tumor immunotherapeutic approaches.

Manganese is a metal with diverse (bio)chemical reactivity in aqueous media in the presence of biologically relevant ligands. Key to that reactivity is the existence of soluble and bioavailable forms of MnII across the physiological range of pH. To probe the interactions arising between MnII and the low-molecular-mass ligand D-(–)-quinic acid, research efforts were targeted at the synthetic aqueous chemistry in the requisite binary system. The pH-specific synthetic reaction of MnII with D-(–)-quinic acid led to the isolation of the new species [Mn2(C7H11O6)4]n·nH2O (1). Complex 1 was characterized by elemental analysis, spectroscopic techniques (EPR, FTIR), thermal and magnetic studies, and X-ray crystallography. The molecular lattice of 1 reveals the presence of dimeric units of MnII centers, with the quinate ligands coordinated to the metal ions through variable binding modes, indicating the diversity of chemical reactivity in the system. The octahedral MnII centers in the molecular assembly of 1 serve as chemical prototypes of the forms of interactions that most likely develop in biologically relevant fluids, similar to those encountered in plant exudates and plant cellular structures. Concurrently, the physicochemical features of 1 (from the 3D hydrogen-bonding network to the magnetic susceptibility properties and EPR spectral results) exemplify the key features that constitute the rudiments of MnII-organic hybrid lattices of specific functions and (bio)chemical reactivity patterns. The collective properties of 1 are discussed in the context of their occurrence in natural binary MnII-influenced systems and advanced metal-hybrid materials of potential applications. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The presence of cobalt in biological systems has been associated with a variety of regulatory roles as an inorganic cofactor. Its involvement in (bio)chemical processes, where it contributes to the integrity of the physiology of humans, underscores its ability to promote (bio)chemistry with molecular targets of variable mass and biological properties. Given the fact that organic phosphonates are widespread substrates/ligands in biological fluids, we sought to investigate the relevant chemistry with CoII. With the organophosphonate ligand N,N-bis(phosphonomethyl)glycine (H5NTA2P) as the main metal ion binder, aqueous reactions with CoII were examined, ultimately leading to the isolation of the complex [Co(C4H9O8NP2)(H2O)2]·2H2O (1) at pH 1.5. This complex was characterized analytically, spectroscopically (FT-IR, UV/Vis, EPR), magnetically, and by cyclic voltammetry. X-ray crystallography shows that 1 is a compound with a molecular type of lattice. The complex consists of a mononuclear, octahedral CoII center coordinated by oxygen atoms belonging to the terminal phosphonate and carboxylate groups of H3NTA2P2–, the ligand nitrogen, and two bound water molecules. It should be emphasized that similar structural features have been observed in other metal organophosphonate lattices of materials with potential catalytic and chemical reactivity. The magnetic and EPR data for 1 suggest the presence of a high-spin octahedral CoII, with a ground state of an effective spin S = 1/2. The solution UV/Vis and EPR spectra suggest retention of the integrity of 1, which is consistent with the magnetization measurements in the solid state. Collectively, the data suggest a soluble CoII–organodiphosphonate species, not unlike those expected in bio-fluids containing the specific ligand or ligands structurally akin to H3NTA2P2–.The biological relevance of 1 to species in bio-fluids and the structural association with CoII–organophosphonate materials is discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Potentiometric, 1H, 31P NMR spectroscopic and X-ray studies were carried out to investigate the complex formation of Al(iii) with iminodiacetic acid (IDA), nitrilotriacetic acid (NTA), their mixed carboxylic–phosphonic and purely phosphonic derivatives. The stability constants of the complexes formed were determined at 25 °C and at 0.2 mol dm−3 ionic strength (KCl). It was found that substitution of CO₂− by PO₃2− increases the overall stability of the complexes, due to the higher basicity of the phosphonic groups. However, the higher spatial requirement of the phosphonic moiety and the greater electrostatic repulsion between the dinegatively charged PO₃2− moieties overcompensate this effect, resulting in a somewhat weaker metal binding capacity for the phosphonic derivatives. According to the 1H NMR spectra of Al(iii) complexes of IDA, complex formation renders the two protons of each CH₂ group inequivalent, while the CH₂ groups of NTA and its derivatives remain chemically and magnetically equivalent in their Al(iii) complexes. As no symmetrical arrangements of the donor atoms in their Al(iii) complexes can be expected with most of the ligands, the rate of intramolecular rearrangement motions of the binding functional groups seems to be different for the IDA and the NTA derivatives.

A representative set of vanadium(IV and V) compounds in varying coordination environments has been tested in the concentration range 1 to 10–6mM, using transformed mice fibroblasts (cell line SV 3T3), with respect to their short-term cell toxicity (up to 36 hours) and their ability to stimulate glucose uptake by cells. These insulin-mimetic tests have also been carried out with non-transformed human fibroblasts (cell line F26). The compounds under investigation comprise established insulin-mimetic species such as vanadate ([H2VO4]–), [VO(acetylacetonate)2], [VO2(dipicolinate)]–and [VO(maltolate)2], and new systems and coordination compounds containing OO, ON, OS, NSand ONSdonor atom sets. A vitality test assay, measuring the reduction equivalents released in the mitochondrial respiratory chain by intracellular glucose degradation, is introduced and the results are counter-checked with 3H-labelled glucose. Most compounds are toxic at the 1 mM concentration level, and most compounds are essentially non-toxic and about as effective as or more potent than insulin at concentrations of 0.01 mM and below. VVcompounds tend to be less toxic than VIV compounds, and complexes containing thio functional ligands are somewhat more toxic than others. Generally, ONligation is superior in insulin-mimetic efficacy to OOor O/NScoordination, irrespective of the vanadium oxidation state. There is, however, no striking correlation between the nature of the ligand systems and the insulin-mimetic potency in these cell culture tests, encompassing 41 vanadium compounds, the results on 22 of which are reported in detail here. The syntheses and characteristics of various new compounds are provided together with selected speciation results. The crystal and molecular structures of {[VO(naph-tris)]2} [where naph-tris is the Schiff base formed between o-hydroxynaphthaldehyde and tris(hydroxymethyl)amine] are reported. Electronic supplementary material to this paper can be obtained by using the Springer Link server located at http://dx.doi.org/10.1007/s00775-001-0311-5

Reactive oxygen species (ROS) have been widely known to inflict biological damage upon a variety of biological sites. The ability to counteract any such activity has been the subject of this work, in an attempt to comprehend prooxidant metal ion induced oxidation and its possible physiological consequences. Five Mediterranean aqueous herb infusions have been employed in the investigation of possible pro/antioxidant activity promoted by prooxidant iron ions. In the presence of phospholipid liposomes or linoleic acid micelles or 2-deoxy-d-ribose, it was shown that all of the aqueous infusions used exhibited antioxidant activity in comparison to the iron control. The antioxidant activity, studied on 2-deoxy-d-ribose, at three concentration levels in each herb, appears to be dose dependent, albeit non-linear. The total polyphenol content of the investigated herb infusions, however, does not directly correlate with the observed antioxidant activity. The variable, yet effective, antioxidant capacity of the aqueous infusions indicates that their antioxidant components can quench ROS generating activity, brought on different substrates and likely arisen by variable mechanisms involving different ROS.

Citric acid represents a class of carboxylic acids present in biological fluids and playing key roles in biochemical processes in bacteria and humans. Its ability to promote diverse coordination chemistries in aqueous media, in the presence of metal ions known to act as trace elements in human metabolism, earmarks its involvement in a number of physiological functions. Cobalt is known to be a central element of metabolically important biomolecules, such as B₁₂, and therefore its biospeciation in biological fluids constitutes a theme worthy of chemical and biological perusal. In an effort to unravel the aqueous chemistry of cobalt in the presence of a physiologically relevant ligand, citrate, the first aqueous, soluble, mononuclear complex has been synthesized and isolated from reaction mixtures containing Co(II) and citrate in a 1 :2 molar ratio at pH~8. The crystalline compound (NH₄)₄[Co(C₆H₅O₇)₂] (1) has been characterized spectroscopically (UV/vis, EPR) and crystallographically. Its X-ray structure consists of a distorted octahedral anion with two citrate ligands fulfilling the coordination requirements of the Co(II) ion. The magnetic susceptibility measurements of 1 in the range from 6 to 295 K are consistent with a high-spin complex containing Co(II) with a ground state S=3/2. Corroborating this result is the EPR spectrum of 1, which shows a signal consistent with the presence of a Co(II) system. The spectroscopic and structural properties of the complex signify its potential biological relevance and participation in speciation patterns arising under conditions consistent with those employed for its synthesis and isolation.

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Among the new members (IIIa)‐(IIIc) of the prismane series prepared, the cluster (IIIa) ( P21/n, Z=4) is investigated by X‐ray diffraction.

The synthesis of the title complexes is achieved by metathetical stoichiometric reactions which occur in MeCN readily under strictly anaerobic and moisture‐free conditions between the anion of (I) and the alkali‐metal salts of the ligands.

The title cluster (III), obtained from the known linear trimer (I), contains Fe in a formal oxidation state of +2.67, determined from the isomer shift in the Moessbauer spectrum.

The title compounds (III) are prepared under strictly anaerobic and moisture‐free conditions.

The Moessbauer spectra of the title clusters, prepared in nearly quantitative yield as shown in the scheme, have been investigated at temp. in the range from 1.6 K to room temperature.

The crystalline title complexes (I) are obtained by the anaerobic reaction of equimolar amounts of NEt4Cl, the Na salt of p‐cresol, and the appropriate anhydrous, bivalent metal chlorides in refluxing, dry MeCN.

The X‐ray isomorphous title clusters (Ib) and (Ic) are obtained by 1:1 molar reaction of the analogous tetraanions (Ia) with ferricinium hexafluorophosphate in similar yields as the chloro derivative (Ib) on the 4:1 molar reaction of the Fe6 cluster (II) with the Mo monomer (III).