Alan Shaver

Fluxional organometallic molecules

Abstract The crystal structure and low temperature PMR spectra of the diironhexacarbonyl adduct of bicyclo[6.2.0]deca-1,3,5-triene have been determined. The entire body of data suggests that the ground state structure of the molecule is of the asymmetric cis-(1,2,6-trihapto-3,4,5-trihapto-cyclooctatriene)diironhexacarbonyl type previously found in (cyclooctatriene)diironhexacarbonyl and (cyclooctatetraene)diruthenium hexacarbonyl. Below −70° the PMR spectrum broadens and the complex spectrum in the slow exchange limit (−130°) is consistent with such an instantaneous structure. Above −70° the spectrum is indicative of a time-average plane of symmetry resulting from fluxionality of the molecule.Abstract The crystal structure and low temperature PMR spectra of the diironhexacarbonyl adduct of bicyclo[6.2.0]deca-1,3,5-triene have been determined. The entire body of data suggests that the ground state structure of the molecule is of the asymmetric cis-(1,2,6-trihapto-3,4,5-trihapto-cyclooctatriene)diironhexacarbonyl type previously found in (cyclooctatriene)diironhexacarbonyl and (cyclooctatetraene)diruthenium hexacarbonyl. Below −70° the PMR spectrum broadens and the complex spectrum in the slow exchange limit (−130°) is consistent with such an instantaneous structure. Above −70° the spectrum is indicative of a time-average plane of symmetry resulting from fluxionality of the molecule.

Peroxovanadium compounds: Biological actions and mechanism of insulin-mimesis

When used alone, both vanadate and hydrogen peroxide (H2O2) are weakly insulin-mimetic, while in combination they are strongly synergistic due to the formation of aqueous peroxovanadium species pV(aq). Administration of these pV(aq) species leads to activation of the insulin receptor tyrosine kinase (IRK), autophosphorylation at tyrosine residues and inhibition of phosphotyrosine phosphatases (PTPs). We therefore undertook to synthesize a series of peroxovanadium (pV) compounds containing one or two peroxo anions, an oxo anion and an ancillary ligand in the inner co-ordination sphere of vanadium, whose properties and insulin-mimetic potencies could be assessed. These pV compounds were shown to be the most potent inhibitors of PTPs yet described. Their PTP inhibitory potency correlated with their capacity to stimulate IRK activity. Some pV compounds showed much greater potency as inhibitors of insulin receptor (IR) dephosphorylation than epidermal growth factor receptor (EGFR) dephosphorylation, implying relative specificity as PTP inhibitors. Replacement of vanadium with either molybdenum or tungsten resulted in equally potent inhibition of IR dephosphorylation. However IRK activation was reduced by greater than 80% suggesting that these compounds did not access intracellular PTPs. The insulin-like activity of these pV compounds were demonstrablein vivo. Intra venous (i.v.) administration of bpV(pic) and bpV(phen) resulted in the lowaring of plasma glucose concentrations in normal rats in a dose dependent manner. The greater potency of bpV(pic) compared to bpV(phen) was explicable, in part, by the capacity of the former but not the latter to act on skeletal muscle as well as liver. Finally administration of bpV(phen) and insulin led to a synergism, where tyrosine phosphorylation of the IR β-subunit increased by 20-fold and led to the appearance of four insulin-dependentin vivo substrates. The insulin-mimetic properties of they pV compounds raises the possibility for their use as insulin replacements in the management of diabetes mellitus.

From Vanadis to Atropos: vanadium compounds as pharmacological tools in cell death signalling

Vanadium compounds exert a variety of biological responses, the most notable being their effects as insulin mimetics. More recently, they have been used as pharmacological tools to investigate signalling pathways. Some peroxovanadium compounds act as powerful protein tyrosine phosphatase inhibitors, modulating both the extent and duration of phosphotyrosine signals at the level of the transmembrane growth factor receptors and targets in the cytoplasm and nucleus. A brief history of vanadium compounds, selected chemical properties of vanadium compounds and the ability of peroxovanadium complexes to modulate the activities of protein tyrosine phosphatases and tyrosine kinases are presented in this review by Anne Morinville, Dusica Maysinger and Alan Shaver. From the range of biological activities of these compounds, this review focuses on cytotoxic effects and possible roles of mitogen-activated protein kinases in mediating the effects exerted by vanadium compounds.

The chemistry of peroxovanadium compounds relevant to insulin mimesis

The inorganic coordination chemistry of peroxovanadium compounds relevant to insulin mimesis is reviewed. The structure and kinetic reactivity of solutions of vanadate anion, vanadyl complexes and peroxovanadate complexes are briefly compared. Peroxovanadium compounds contain an oxo group, one or two peroxo ligands (O22−) and an ancillary ligand which is usually bidentate. These compounds approximate a trigonal bipyramidal structure which can be divided conceptually into a polar ‘oxo’ half and a relatively non-polar organic half. This presents a number of interesting design variations which are discussed with respect to the development of a rudimentary structure-activity correlation of insulin mimetic ability.

Bisperoxovanadium compounds: synthesis and reactivity of some insulin mimetic complexes☆

Abstract A series of bisperoxovanadium complexes (bpV) of the general formula K3[VO(O2)2(L-L′)] has been prepared and characerized. where L-L′ is a pyridinedicarboxylate (2,3-pdc, 2,4-pdc, 2,5-pdc) or 3-acetatoxypicolinate (3-acetpic). Two structures have been determined: bpV(2,4-pdc), P21, a = 38.187(5) A , c = 11.4088(8) A , β = 90.546(9)° , V = 3093.8(7) A 3 , Z = 8, R/Rw = 0.049/0.055, and bpV(3-acetpic), P1, a = 7.4037(13) A , b = 10.709(3) A , c =10.9569(19) A , α = 110.742(16)°, β = 95.600(19)°, γ = 100.195(19)°, V = 787.4(3) A 3 , Z = 2, R/Rw=0.036/0.026. The oxygen atom of the 2-carboxylate group and the oxo ligand are situated in apical positions of a pseudotrigonal plane formed by the nitrogen atom and the centres of the two peroxo groups. The compounds rapidly oxidize sodium tris(3-sulfonatophenyl)phosphine, in water, to the corresponding oxide. The results are discussed with reference to the reported insulin mimetic activity of this class of compounds.

Preparation of ruthenium silanethiolato complexes and their reactions with sulfur dioxide; possible models for the activation of SO2 in the homogeneously catalyzed Claus reaction

Abstract CpRu(PPh3)2SSiiPr3 (6a) was prepared by reacting [CpRu(PPh3)2(acetone)]BF4 and NaSSiiPr3. Complex 6a is substitution-labile and readily gave the mixed-ligand derivatives CpRu(PPh3)(L)SSiiPr3, where L=CO (6b), PMe3 (6c), P(OMe)3 (6d), upon treatment with the corresponding ligands. CpRu(dppe)SSiiPr3 (6e) was obtained from complex 6a and dppe via the intermediate formation of CpRu(PPh3)(η1-dppe)SSiiPr3. Treatment of complex 6a with one equivalent of SO2 gave primarily unstable CpRu(PPh3)(SO2)SSiiPr3 (6f). However, complexes 6b–e inserted one equivalent of SO2 solely at their SSiiPr3 function to give the unstable O-silyl thiosulfito complexes CpRu(PPh3)(L)SS(O)OSiiPr3 (L=CO (8b), PMe3 (8c), P(OMe)3 (8d)) as well as CpRu(dppe)SS(O)OSiiPr3 (8e). The SH bonds of CpRu(PPh3)2SH (7a) and CpRu(dppe)SH (7b) added to PhNSO to give CpRu(PPh3)2SS(O)NHPh (9a) and CpRu(dppe)SS(O)NHPh (9b), respectively. The crystal structure of complex 6a was determined. Crystallographic data for 6a: triclinic, P1, a=10.642(6) A, b=11.068(8) A, c=21.994(10) A, α=79.27(5)°, β=89.22(5)°, γ=62.32(4)°, V=2246(2) A3, Z=2.

Complexes of polypyrazolylborate ligands : I. Conformational isomerism in [tetrakis(1-pyrazolyl)borate] h5-cyclopentadienyl)dicarbonylmolybdenum

Abstract Studies on the structure of [B(pz) 4 ](C 5 H 5 )(CO) 2 Mo, where B(pz) 4 represents the tetrakis(pyrazolyl)borate group, have shown that the B(pz) 4 ligand is bidentate, while the cyclopentadienyl group is pentahapto . The interesting six-membered metallocyclic ring can exist in two conformers in solution, and these interconvert, with an activation energy of the order of 10 kcal/mol, thus giving rise to extensive variations in the proton NMR spectrum as the temperature is varied.

Catenated polysulfur ligands: the pentasulfides of di-η5-cyclopentadienyl-zirconium(IV) and -hafnium(IV)

Abstract The thiols Cp 2 M(SH) 2 , where M = Ti and Zr, react to form the complexes Cp 2 MS 5 when treated with mono- and di-sulfur transfer reagents. Treatment of Cp 2 MCl 2 with Li 2 S 2 and sulfur gave Cp 2 MS 5 , M = Ti, Zr and Hf, in better yield. The new Zr and Hf complexes have a six-membered MS 5 ring in a chair conformation similar to the previously observed for M = Ti. Variable temperature NMR studies show that the barriers to MS 5 ring inversion decrease in the order Ti > Hf > Zr.

Activation of MAPK by potassium bisperoxo(1,10-phenanthroline)oxovanadate (V)

Potassium bisperoxo(1,10-phenantroline)oxovanadate (V) [bpV(phen)] is a potent protein tyrocine phosphatase inhibitor which mediates a variety of biological effects. The aim of these studies was to examine the role(s) of mitogen activated protein kinase (MAPK) pathways in PC12 cell proliferation and toxicity by bpV(phen). BpV(phen) exerts a bimodal effect in PC12 cells: proliferation at low and cell death at higher micromolar concentrations. Activation of MAPK by bpV(phen) depends on time and concentration. The phosphorylation pattern of extracellular regulated kinases (ERK 1/2), c-jun N-terminal activated kinases (JNK) and p38 in PC12 cells is strikingly different. Activation of JNK is sustained in PC12 cells. In contrast, ERK 1/2 activation is transient and treatment with PD98059 indicates that ERK activation by bpV(phen) is partly independent from the ras-MEK pathway. Stability studies of bpV(phen) in DMEM and PBS showed linear relationship with T1/2 about 6 h and 10 days in DMEM and PBS, respectively. Comparison between the time courses of MAPK activation and kinetics of bpV(phen) decomposition as assessed by 51V-NMR analysis show that the initial and maximal phosphorylation signals are produced in the presence of the complex bpV(phen) and not caused by the decomposition products of bpV(phen).

Complexes of Polypyrazolylborate ligands : III. Structure of [dihydrobis(3,5-dimethyl-1-pyrazolyl) borate](h3-cycloheptatrienyl)dicarbonylmolybdenum in solution☆

Abstract Studies of the structure of [H 2 B(3,5-MePz) 2 ](C 7 H 7 )(CO) 2 Mo and [Et 2 B(Pz) 2 ](C 7 H 7 )(CO) 2 Mo, where H 2 B(3,5-Me 2 Pz) 2 and Et 2 B(Pz) 2 represent dihydrobis(3,5-dimethyl-1-pyrazolyl)borate and diethyldipyrazolylborate groups respectively, have been carried out on solutions using infrared and PMR spectra. The data indicate that the C 7 H 7 groups are trihapto and the pyrazolylborate groups are bidentate giving rise to novel complexes that manifest a variety of modes for stereochemical nonrigidity.