Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat

For many years proof that the hypoxic nature of malignant tumours can be used to selectively target anticancer drugs has been sought. Several classes of potential redox activated anticancer drugs have been developed to take advantage of the reducing environment resulting from the hypoxia. Drug complexes with redox active metal centres as carriers have been investigated, but have largely been employed with cytotoxic drugs that require release of the drug intracellularly, complicating the design of such complexes. MMP inhibitors, a new class of anticancer drug, conversely act in the extracellular environment and we have investigated inhibitor complexes with several redox active transition metals. Marimastat is an MMP inhibitor with potent in-vitro antimetastatic activity and was recently in Phase III clinical trials for a variety of cancer types. We have synthesised a Co(II1) complex of marimastat incorporating the tetradentate ligand tpa (tris(2-methylpyridyl)amine) as a carrier ligand. The complex was structurally characterised in the solid state by single crystal X-ray diffraction, the first example of a crystal structure containing marimastat. 2D COSY and NOESY NMR spectra showed that the complex exists in two isomeric forms in solution, corresponding to the cis and trans isomers yet only crystallises in one of these forms. Biological testing of the complex in mice with 4T1.2 tumours showed interesting and unexpected outcomes. Initial results of the tumour growth inhibition study showed that a significant inhibition of growth was exhibited by the complex over the free inhibitor and the control. However, the metastatic potential of both free marimastat and the complex were higher than the control indicating likely problems with the experimental protocol. Further experiments are needed to determine the potential of such complexes as hypoxia activated prodrugs but there appears at least to be some promise.

Visual biology of Hawaiian coral reef fishes. II. Colors of Hawaiian coral reef fish

The colors of 51 species of Hawaiian reef fish have been measured using a spectrometer and therefore can be described in objective terms that are not influenced by the human visual experience. In common with other known reef fish populations, the colors of Hawaiian reef fish occupy spectral positions from 300-800nm; yellow or orange with blue, yellow with black, and black with white are the most frequently combined colors; and there is no link between possession of ultraviolet (UV) reflectance and UV visual sensitivity or the potential for UV visual sensitivity. In contrast to other reef systems, blue, yellow, and orange appear more frequently in Hawaiian reef fish. Based on spectral quality of reflections from fish skin, trends in fish colors can be seen that are indicative of both visually driven selective pressures and chemical or physical constraints on the design of colors. UV-reflecting colors can function as semiprivate communication signals. White or yellow with black form highly contrasting patterns that transmit well through clear water. Labroid fishes display uniquely complex colors but lack the ability to see the UV component that is common in their pigments. Step-shaped spectral curves are usually long-wavelength colors such as yellow or red, and colors with a peak-shaped spectral curves are green, blue, violet, and UV.

Embracing ligands. A synthetic strategy towards new nitrogen-thioether multidentate ligands and characterization of the cobalt(III) complexes

The synthesis of the hexadentate ligand 2,2,9,9-tetra(methyleneamine)-4,7-dithiadecane (EtN(4)S(2)amp) is reported. The ligand is of a type in which bifurcations of the chain occur at atoms other than donor atoms. The cobalt(III) complex [Co(EtN(4)S(2)amp)](3+) (1) was isolated and characterized. The synthetic methodology also results in a number of by-products, notably 2,9,9-tris(methyleneamine)-9-methylenehydroxy-4,7-dithiadecane (Et(HO)N(3)S(2)amp) and an eleven-membered pendant arm macrocyclic ligand 6,10-dimethyl-6,10-bis(methyleneamine)-1,4-dithia-8-azaacycloundec-7- ene (dmatue). The complexes [Co(Et(HO)N(3)S(2)amp)](3+) (2), in which the alcohol is coordinated to the metal ion, and [Co(dmatue)Cl](2+) (4) were isolated and characterized. Et(HO)N(3)S(2)amp also undergoes complexation with cobalt(III) to produce two isomers endo-[Co(Et(HO) N(3)S(2)amp)Cl](2+) (endo-3) and exo-[Co(Et(HO) N(3)S(2)amp)Cl](2+) (exo-3), both with an uncoordinated alcohol group. endo- 3 has the alcohol positioned cis, and exo-3 trans, to the sixth metal coordination site. Reaction of 1 with isobutyraldehyde, paraformaldehyde and base in dimethylformamide results in the encapsulated complex [Co(1,5,5,9,13,13-hexamethyl-18,21-dithia-3,7,11,15-tetraazabicyclo[7.7.6]docosa- 3,14-diene)](ClO4)(3) . 2H(2)O ([Co(Me(6)docosadieneN(4)S(2))](3+) ( 5). All complexes have been characterized by single crystal X-ray study. The low-temperature (11 K) absorption spectrum of 1 has been measured in Nafion films with spin-allowed (1)A(1g) --> T-1(1g) and (1)A(1g) --> T-1(2g) and spin forbidden (1)A(1g) --> T-3(1g) and (1)A(1g) --> T-3(2g) bands observed. The octahedral ligand-field parameters were determined (10Dq = 22570 cm(-1), B = 551 cm(-1); C = 3500 cm(-1)). For 5 10Dq and B were determined (20580 cm(-1); 516 cm(-1), respectively) and compared with those for similar expanded cavity complexes [Co(Me(8)tricosatrieneN(6))](3+) and [Co(Me(5)tricosatrieneN(6))](3+).

Continental extension: From core complexes to rigid block faulting

Extension of overthickened continental crust is commonly characterized by an early core complex stage of extension followed by a later stage of crustal-scale rigid block faulting. These two stages are clearly recognized during the extensional destruction of the Alpine orogen in northeast Corsica, where rigid block faulting overprinting core complex formation eventually led to crustal separation and the formation of a new oceanic backarc basin (the Ligurian Sea). Here we investigate the geodynamic evolution of continental extension by using a novel, fully coupled thermomechanical numerical model of the continental crust. We consider that the dynamic evolution is governed by fault weakening, which is generated by the evolution of the natural-state variables (i.e., pressure, deviatoric stress, temperature, and strain rate) and their associated energy fluxes. Our results show the appearance of a detachment layer that controls the initial separation of the brittle crust on characteristic listric faults, and a core complex formation that is exhuming strongly deformed rocks of the detachment zone and relatively undeformed crustal cores. This process is followed by a transitional period, characterized by an apparent tectonic quiescence, in which deformation is not localized and energy stored in the upper crust is transferred downward and causes self-organized mobilization of the lower crust. Eventually, the entire crust ruptures on major crosscutting faults, shifting the tectonic regime from core complex formation to wholesale rigid block faulting.

Gold(III) template synthesis of a pendant-arm macrocycle

Gold(III)-directed condensation of ethane-1,2-diamine with nitroethane and formaldehyde yielded the gold-coloured macrocyclic complex (cis-6,13-dimethyl-6,13-dinitro-1,4,8,11-tetraazacyclotetradecan-1-ido)gold(III) and the orange acyclic complex (1,9-diamino-5-methyl-5-nitro-3,7-diazanoran-3-ido)gold(III) in good yields. Dissolution in strongly acidic solution gave the colourless fully protonated complexes. The pendant nitro groups are disposed on the same side of the macrocycle in a cis geometry, as confirmed by crystal structure analysis. In both complexes the gold ion lies in a square-planar environment of four nitrogen donors, and the co-ordinate bond to the deprotonated amine is shorter than the remaining Au-N distances.

A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice

The class II major histocompatibility complex molecule I-A(g7) is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its beta chain. To identify the requirements for peptide binding to I-A(g7) and thereby potentially pathogenic T cell epitopes, we analyzed a known I-A(g7)-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9-27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-A(g7) M12-Y20/K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-A(g7) deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-A(g7)-restricted T cell epitopes or eluted from I-A(g7). Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.

Electron paramagnetic resonance of Ni(II) doped tris(ethylenediamine)zinc(II) dinitrate

Variable temperature electron paramagnetic resonance spectra of tris(ethylenediamine)zinc(II) dinitrate single crystals doped with NI(II) have been measured. The host crystal undergoes a trigonal to monoclinic phase transition at 146 K. Above the transition temperature the zero field splitting tensor is axially symmetric with D = -0.831 cm(-1) and below it becomes rhombic with D = -0.785 cm(-1), E = -0.088 cm(-1). The low temperature spectrum is characterised by the pattern repeating every 60 degrees when the crystal is rotated about the high temperature c axis. The analysis shows that the Zn(II) site retains a C-2 symmetry axis and that the distortion away from the D-3 site symmetry observed for high temperatures is small, the principal axes being tilted by 2.6 degrees. This implies that the phase transition involves the flipping of the C-C backbone in one of the ethylenediamine ligands of the complex, resulting in a A delta delta delta to Lambda delta delta lambda type conformational change.