Grant N. Holder

Pharmacokinetic and endocrinological parameters of a slow-release depot preparation of the GnRH analogue ICI 118630 (Zoladex) compared with a subcutaneous bolus and continuous subcutaneous infusion of the same drug in patients with prostatic cancer

SummarySeventeen patients with advanced prostatic cancer were treated with the gonadotrophin-releasing hormone analogue DSer (tBU)6 AzaGly10 GnRH (ICI 118630), either as a constant SC infusion, or in the form of a monthly SC slowrelease depot formulation, in which case patients were randomised to receive one of three doses. Six of these patients also received a 250-μg SC bolus of ICI 118630, for pharmacokinetic studies, before starting the infusion or the depot. Drug levels were measured using a bouble-antibody radioimmunoassay. In contrast to the SC infusion, which gave a smooth serum 118630 level profile, drug release from the depot preparation was not constant, levels varying in a predictable manner throughout each 28-day period, reaching a peak proportional to the dose of ICI 118630 received, between days 15 and 18 of each cycle. With all methods of administration there was an initial rise in LH, usually followed by a rise in testosterone, after which the SC infusion and the depot were both effective in reducing serum LH to basal levels and testosterone into the castrate range within 1 month.It is too early to make any assessment of clinical response; however, depot treatment was well tolerated: Four patients experienced an initial flare in bone pain, probably related to the initial rise in testosterone, and twelve patients experienced flushing; one patient with pre-existing hydronephrosis and hydroureter developed renal failure, possibly related to a tumour flare reaction. No patients have experienced cardiovascular side effects or local reaction.

Voltammetry of monomeric and dimeric oxorhenium(V) complexes of Schiff base ligands N,N′-ethylenebis(acetylacetone)diimine, N,N′-ethylene(salicylidene)diimine and N,N′-phenylenebis(salicylidene)diimine

Abstract The electrochemical study of six Schiff base complexes of oxorhenium(V) of the general formula Re2O3L2 and ReOClL (L=N,N′-ethylenebis(acetylacetone)diimine (acacen), N,N′-ethylene(salicylidene)diimine (salen) and N,N′-phenylenebis(salicylidene)diimine (salphen)) was undertaken. In non-aqueous media the oxorhenium(V) monomers exhibit an equilibrium in solution (between forms ReOClL and [ReOL]++Cl−), the position of the equilibrium dependent on L. A one-electron reduction and one-electron oxidation are observed, followed by a fast chemical reaction, resulting in decomposition of the complex. The μ-oxo dimeric complexes underwent a two-electron reduction followed by decomposition to an electroinactive product. Successive one-electron oxidations of each rhenium in Re2O3L2 were observed. Each electron-transfer step was coupled to a chemical reaction; the generation of [Re2O3L2]+ was followed by the cleavage of the μ-oxo bond and formation of mono-oxo species. This reaction was much slower than the decomposition which followed generation of [Re2O3L2]2+.

Structural and electronic properties of (2,2-trans)-dirhodium(II) tetrakis(N-phenylacetamidate)

Abstract We have synthesized and characterized the first known 2,2-trans isomer of the N-substituted dirhodium(II) tetrakisacetamidate, Rh2(RNAc)4, class of compounds. The bis benzonitrile adduct exhibits a unique orthogonal arrangement of the axial aromatic rings in the solid state. Structural and electronic features suggest the presence of π-backbonding.

Electron-transfer behaviour of oxorhenium(V), nitridorhenium(V) and rhenium(III) diethyldithiocarbamate complexes

Abstract The voltammetric behaviour of ReN(S2CN(Et)2)4, Re(S2CN(Et)2)3, ReOX(S2CN(Et)2)2, where X=Cl or Br, and Re2O3(S2CN(Et)2)4, were examined in five non-aqueous solvents. The nitridorhenium(V) complex underwent a non-reversible one-electron reduction followed by a chemical reaction. The rhenium(III) complex underwent a reversible one-electron oxidation to form the Re(IV) species; a second one-electron oxidation was followed by decomposition. The oxorhenium(V) monomers exhibit an equilibrium in solution between ReOX(S2CN(Et)2)2 and [ReO(S2CN(Et)2)]++X−. Reduction of the latter caused severe electrodeposition which could be observed with the naked eye; the deposited material was non-conducting. The position of the equilibrium depended strongly on the identity of X−. The potentials were strongly solvent dependent, with deposition of ReO(S2CN(Et)2)2 greatly reduced in the presence of electron-donating solvents. The anodic behaviour of Re2O3(S2CN(Et)2)4 consisted of a one-electron process which was followed rapidly by cleavage of the μ-oxo bridge to form [ReO(S2CN(Et)2)2]+ and ReO2(S2CN(Et)2)2.

cis-Enhanced cyclopropanation catalysts: reaction chemistry of three isomers of Rh2[N(C6H5)COCH3]4

Abstract The catalytic activities of three structural isomers of Rh 2 [N(C 6 H 5 )COCH 3 ] 4 in cyclopropanation reactions were surveyed. These studies showed cis cyclopropanation selectivity with bulky alkenes for 2,2- cis - and 2,2- trans -Rh 2 [N(C 6 H 5 )COCH 3 ] 4 .

Voltammetry of oxorhenium(V) complexes containing the [O=Re−OR] core and substituted pyridine ligands

SummaryCompounds of the general formula [ORe(OR)Cl2(PPh3)2] and [ORe(OEt)Cl2(PPh3)(py)], where R=alkyl or aryl and py=a substituted pyridine, were synthesized and their voltammetric behaviour investigated. For the former, the electron-transfer mechanism was observed to be dependent on solvent. In dry MeCN, a quasi-reversible oxidation and a reduction followed by a chemical reaction was observed. There were indications of nucleophilic attack on electrochemically generated [ORe(OEt)Cl2(PPh3)2]+, forming an unstable species whose reduction potentials were strongly dependent on the identity of the nucleophile. Voltammetric and spectroscopic observations of the oxorhenium(V) alkoxypyridine complex indicate the pyridine to be labile in halogenated hydrocarbon solvents but not in Me2CO, MeCN, or CCl4. Electrochemical generation of [ORe(OEt)Cl2(PPh3)(ClxCyHz)]+ (x=1,2, or 3; y=1 or 2; z=2,3, or 4) appears to be followed by transfer of a hydrogen atom from the solvent to form [(HO)Re(OEt)Cl2(PPh3)]+. Various pyridine complexes of this type were preparedvia substitution reactions under mild conditions. Varying the reaction conditions allowed the synthesis oftrans-dioxotetrapyridyl complexes in excellent yield.

Electrochemical studies of bimetallic rhenium(III) complexes possessing two accessible mixed-valence states

SummaryBimetallic complexes of the general formula [Cl3(PPh3)2ReIII(NC―Ar―CN)ReIII(PPh3)2Cl3] (where NC―Ar―CN represents an aromatic dinitrile) have been prepared and their solution phase electrochemistry examined. Each of these complexes undergoes two one-electron metal-centred oxidations. The potential difference between these oxidations gives a measure of the stability of the ReIII/ReIV mixed-valence state toward disproportionation, and ranges from <0.050 V in the most weakly coupled system (4,4′-biphenyldicarbonitrile bridge) to ca. 0.200 V for the most strongly interacting metal centres (9,10-dicyanoanthracene bridge). Likewise, all of the complexes show two one-electron transfers in either simultaneous or sequential fashion depending on the nature of the bridge.

Redox tuning of mononuclear rhenium(III) complexes containing substituted nitrile andpara-substituted triphenylphosphine ligands

SummaryA series of oxorhenium(V) complexes of general formula ReOCl3[(4-RC6H4)3P]2 was prepared and converted into rhenium(III) complexes of general formula ReCl3(MeCN)[(4-RC6H4)3P]2. Replacement of the coordinated acetonitrile in the complex ReCl3(MeCN)(Ph3P)2 by a series ofpara-substituted benzonitriles yielded complexes of general formula ReCl3(4-RC6H4CN)(Ph3P)2. The voltammetric behavior of these oxorhenium(V) and rhenium(III) complexes was characterized. For all three classes of compounds, reversible one-electron oxidations and reductions were observed. The redox potentials were correlated with the pKa of the substituted phosphine and with the Hammett-Taft constants for both the phosphine and benzonitrile substituent.

Kinetic and electrochemical study of nitrile adducts of tetrachloro-bis (1,2-bis(diphenylphosphine)methane)dirhenium(II)

SummaryThe addition of two nitrile ligands to the complex Re2Cl4-(dppm)2 (dppm= 1,2-bis(diphenylphosphine)methane)in CH2Cl2 solution has been investigated electrochemically. Upon addition of one equivalent of nitrile NCR (R = aromatic or aliphatic group) to the CH2Cl2/0.1mtetra-N-butylammonium hexafluorophosphate (TBAH) solution, Re2Cl4(dppm)2(NCR) is formed immediately, without dissociation of chloride; electrochemical investigation indicates this nitrile addition is reversible upon oxidation of the dirhenium complex. On addition of two or more equivalents of nitrile, a slow ligand substitution takes place with addition of a second nitrile and concomitant loss of a chloride ion to form [Re2Cl3-(dppm)2(NCR)2]+. The rate of addition of nitrile to Re2Cl4(dppm)2(NCR) appears to depend on the electrondonating or electron-withdrawing abilities of the ligand. The change from monoadduct to diadduct was followed with differential pulse voltammetry for various concentrations of added nitrile. The addition was found to be first order in nitrile.