John T. Edward

Partial molar volumes of organic compounds in water. III. Carbohydrates

Partial molar volumes in water at 25°C have been determined for a number of carbohydrates, including mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, and polysaccharides and their derivatives. The experimental values can be calculated from the van der Waals volumes of the molecules if account is taken of the shrinkage in volume caused by hydrogen-bonding of solvent molecules to the hydroxyl groups of the sugars.

Effect of pyridoxal isonicotinoyl hydrazone and other hydrazones on iron release from macrophages, reticulocytes and hepatocytes

A model consisting of 59Fe-labelled macrophages was developed for screening potential iron-chelating drugs. Mouse peritoneal macrophages, induced by previous intraperitoneal injections of 3% thioglycollate, were labelled in vitro by their exposure to immune complexes of 59Fe-transferrin-antitransferrin antibody. Optimal conditions for macrophage labelling and subsequent 59Fe release were established. Sixty-two aromatic hydrazones, the majority of which had iron binding structures similar to pyridoxal isonicotinoyl hydrazone, were synthesized by condensation of aromatic aldehydes (pyridoxal, salicylaldehyde, 2-hydroxy-1-naphthylaldehyde and 2-furaldehyde) with various acid hydrazides prepared by systematic substitutions on the benzene ring. These compounds were examined for their potential to stimulate 59Fe release from 59Fe-labelled macrophages and also from reticulocytes and hepatocytes loaded with non-heme 59Fe. The majority of hydrazones derived from pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde seemed to be equally effective in both the macrophage and reticulocyte testing systems. However, the pyridoxal hydrazones were much more active in hepatocytes than the other groups of hydrazones. Several compounds proved to be very potent in mobilizing 59Fe. These included hydrazones derived from 2-hydroxy-1-naphthylaldehyde and benzoic acid hydrazide, p-hydroxybenzoic acid hydrazide, 2-thiophenecarboxylic acid hydrazide, and also pyridoxal benzoyl hydrazone, pyridoxal m-fluorobenzoyl hydrazone and pyridoxal 2-thiophenecarboxyl hydrazone.

Partial molar volumes of organic compounds in water. Part 1.—Ethers, ketones, esters and alcohols

The partial molar volumes of a number of ethers, ketones, esters and alcohols in water at 25.0°C have been determined and related to their van der Waals volumes by one of two equations, depending on whether the molecules are spherical or cylindrical in shape. Allowance has been made for the void volume associated with each molecule and the results imply that calculated volumes must be reduced by a constant amount for each carbonyl or hydroxyl group present, owing to hydrogen bonding to water. No such reduction in the calculated volume is required for the oxygen atom of an ether. It is shown for diols that the amount of void volume per additional —CH2— group remains constant for straight-chain compounds (i.e., cylinders), whereas for spherical molecules the amount of void volume decreases with increase in the number of carbon atoms, as predicted.

Partial molar volumes of organic compounds in water. Part 2.—Amines and Amides

The partial molar volumes of a variety of aliphatic amines and amides in water at 25°C have been determined, and related to their van der Waals volumes. In accordance with earlier studies the relationship between partial molar and van der Waals volumes is shown to depend upon molecular geometry. Hydrogen bonding to the solvent causes a volume reduction and group contributions (decrements) for such interactions of amines have been obtained. Additivity of group contributions is shown to allow the prediction of partial molar volumes for nitrogen-containing compounds.

Partition coefficients of the iron(III) complexes of pyridoxal isonicotinoyl hydrazone and its analogs and the correlation to iron chelation efficacy

Pyridoxal isonicotinoyl hydrazone and its analogs are orally effective Fe(III) chelators which show potential as drugs to treat iron overload disease. The present investigation describes the measurement of the partition coefficient of the apochelator and Fe(III) complex of 20 of these ligands. These measurements have been done to investigate the relationship between lipophilicity and the efficacy of iron chelation in rabbit reticulocytes loaded with non-heme 59Fe. The results demonstrate a linear relationship between the partition coefficient (P) of the apochelator and its Fe(III) complex, and a simple equation has been derived relating these two parameters. Experimental data in the literature are in agreement with the equation. The relationship of the partition coefficients of the iron chelators and of their Fe(III) complexes to the effectiveness of the ligands in mobilizing iron in vitro and in vivo is also discussed.

Iron chelators of the pyridoxal isonicotinoyl hydrazone class. Relationship of the lipophilicity of the apochelator to its ability to mobilize iron from reticulocytes in vitro: reappraisal of reported partition coefficients

The partition coefficients P between n-octanol and water of pyridoxal isonicotinoyl hydrazone and 34 analogues have been determined experimentally; the values indicate that the partition coefficients calculated for these compounds, and previously reported (P. Ponka, D.R. Richardson, J.T. Edward, and F.L. Chubb. Can. J. Physiol. Pharmacol. 72: 659-666. 1994; D.R. Richardson, E.H. Tran, and P. Ponka. Blood, 86: 4294-4306. 1994), are too low by 2-3 orders of magnitude. The calculations, using Rekkers additive method, failed because the molecules have two or more hydrophilic sites close together. More recent additive schemes (CLOGP, KOWWIN, ACD/LogP) also failed. The only reliable method was the semi-empirical method of Hansch. This requires the experimental determination of the partition coefficient of at least one representative in each series of compounds of related structure. In the present paper, determination of log P of three representatives enabled us to calculate the partition coefficients of the other 32 compounds with acceptable accuracy. The new results show that apochelators have maximum activity in releasing 59Fe from reticulocytes when they have log P = 2.8 (P = 630), and not log P = 0 (P = 1), as reported by Ponka et al. (P. Ponka, D.R Richardson, J.T. Edward, and F.L Chubb. Can. J. Physiol. Pharmacol. 72: 659-666 1994).

Partition coefficients of the iron (III) complexes of pyridoxal isonicotinoyl hydrazone and its analogs and the correlation to iron chelation efficacy. Correction of some reported partition coefficients

Pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehydebenzoyl hydrazone (SBH), and their analogschelate iron(III) and show promise asorally effective drugs for treating diseases of iron overload. Theirbiological activity isrelated to their lipophilicity, as measured by their partition coefficients P betweenn-octanoland water. However, the method of calculating log P described in an article in this journal(Edwardet al. 1995; BioMetals, 8, 209-217) is faulty for compounds such as PIH, SBH andtheir analogs whichcontain adjacent hydrophilic groups. Consequently, the calculations reportedin the article, based on erro-neouslog P values of the chelating molecules, giveerroneous log P values of the iron(III) complexes. Thechelators most effective inmobilizing 59 Fe from reticulocytes have log P < 2.8, not log P < 0 and theiron(III)complexes of the most effective chelators have log P < 3.1, not log P < 0.

Reactions of iron pentacarbonyl with some steroid dienes

Abstract Tricarbonyliron complexes of steroidal Δ 2,4 - and Δ 5,7 -dienes have been prepared. The transoid Δ 3,5 - and Δ 4,6 -dienes, when heated with iron pentacarbonyl, rearrange to form the cisoid Δ 2,4 -diene complexes. Complex formation, followed by liberation of the diene ligand, thus offers a means of converting heteroannular steroidal dienes into their thermodynamically less stable homoannular isomers.

Stereochemical studies. IX. Acid-catalyzed rearrangement of δ- to γ-lactones

Depending on their constitution and stereochemistry, δ-lactones are converted by hot formic acid into pendant or spiro γ-lactones.

Assisted hydrolysis of cis-2-(3-phenylthioureido)cyclo pentane-carbonitrile in alkaline solution. Solvent dependent switch from hydrolysis to rearrangement of the iminothiooxopyrimidine intermediate

The cis and trans isomers of 2-(3-phenylthioureido)cyclopentanecarbonitrile, 1, and the respective carboxamides, 3, and acids, 4, have been prepared. Acid cyclization of both nitriles, faster with the cis isomer, gave the more stable cis-2-thiooxo-cyclopenta[d]pyrimidin-4-one, 7. In base cis-1 formed the cis 4-imino-2-thiooxopyrimidine 2 which in aqueous alkali broke down via 3 to the acid 4; while in the presence of 66% acetonitrile 2 rearranged to the 4-phenyliminopyrimidine 5 to give as final product the thioureido acid 6 carrying no phenyl group. The 1H NMR data for imino and phenylimino derivatives 2 and 5 showed strong bias for conformation A with 1-N pseudoaxial in the cyclopentane ring. Spectra of the E and Z isomers of the iminopyrimidine 2 under slow exchange could be recorded in DMSO-d6. The phenylimino tautomer of 5 is observed in CD3OD and in CDCl3 with the E and Z isomers in a 1:1 ratio. In DMSO-d6 the phenylamino tautomer 5a is also detected. The first process in aqueous KOH, the conversion of nitrile cis-1 into the imino intermediate 2, reaches an equilibrium which shifts towards the nitrile at higher alkalinities because of ionization of the phenylthioureido group (Ke = [2]/[1] = 2.43 and pKAH = 12.74). The cyclization of 1 to 2 is first order in [OH–] while the slower breakdown of 2 is pH independent. The latter is 104 times faster than the hydrolysis of acetonitrile evidencing substantial anchimeric assistance. The change in the reaction route towards the rearranged phenyliminopyrimidine 5 upon addition of acetonitrile can be caused by the lower dielectric constant favouring the elimination step leading to the intermediate isothiocyanate, and by increased activity of OH– accelerating the (presumably) second order elimination step as opposed to the pH-independent hydrolysis of the imino derivative 2.