Norman J. Rose

Cytotoxic chelators and chelates 1. Inhibition of DNA synthesis in cultured rodent and human cells by aroylhydrazones and by a copper(II) complex of salicylaldehyde benzoyl hydrazone

Abstract Aroylhydrazones of pyridoxal and of salicylaldehyde, a series of tridentate chelating agents, are potent inhibitors of DNA synthesis and cell growth in a number of human and rodent cell lines grown in culture. A copper(II) complex of the most potent of the chelators, salicylaldehyde benzoyl hydrazone (SBH), exhibits significantly greater inhibitory activity than does SBH itself. Although the bioactive forms and mechanism of action of these agents are uncertain, their cytotoxic activity can equal or exceed that of many chelators and chelates previously known to possess such properties, including compounds used clinically. SBH and its copper complex are relatively non-toxic to mice and show some measure of selectivity in their effects on different cell types. It is possible that aroylhydrozones of this type and/or their metal complexes could prove to be useful therapeutic agents.

The structure of a copper complex of the growth factor glycyl-L-histidyl-L-lysine at 1.1 Å resolution

Abstract Interest in the crystal structure of a copper complex of the growth factor, glycyl-L-histidyl-L-lysine has been stimulated by the tripeptides ability to facilitate copper uptake in cultured hepatoma cells and by the copper complexs tendency to induce angiogenesis. The coordination polyhedron is a distorted square pyramid, CuN3O2, with the four basal ligating atoms bonded to the copper at about 2.00 A and the apical ligating atom at 2.49 A. One tripeptide furnishes three of the basal atoms, the glycine amino nitrogen atom, the peptide nitrogen atom of the histidine, and the imine nitrogen atom of the imidazole. A second tripeptide is involved via its terminal carboxyl oxygen atom while the fifth copper ligand is a carboxyl oxygen atom of a third tripeptide. The carboxyl oxygen atoms form bridges between copper centers and thus the system is polymeric in the solid state. The crystal structure can be used to propose a model for the first step in the transport of copper into cells via a copper-tripeptide complex.

Syntheses of iron(III) aroyl hydrazones containing pyridoxal and salicylaldehyde. The crystal and molecular structure of two iron(III)-pyridoxal isonicotinoyl hydrazone complexes

Abstract Iron(III) complexes of three aroyl hydrazones, pyridoxal isonicotinoyl hydrazone (H 2 pih), pyridoxal benzoyl hydrazone (H 2 pbh), and salicylaldehyde benzoyl hydrazone (H 2 sbh), were synthesized and characterized. In aqueous medium at pH 7, [Fe(pih)(Hpih)]·3H 2 O is formed. In acidic methanol, a 1:1 ligand-to-metal complex is formed, [FeCl 2 (H 2 pih)]Cl ( 1 ), whereas in aqueous medium at low pH cis -[FeCl 2 (H 2 pih)(H 2 O)]Cl·H 2 O ( 2 ) is formed. Compounds 1 and 2 are high-spin d 5 with μ eff = 5.88 μ B and 5.93 μ B (298 K). The crystal structures of 1 and 2 show that H 2 pih acts as a tridentate neutral ligand in which the phenolic and hydrazidic protons have shifted to the pyridine nitrogen atoms. The co- ordination polyhedron of 1 is ‘square’ pyramidal, whereas that of 2 is pseudo-octahedral. Compound 1 is triclinic, space group P l , with a = 12.704(2) A, b = 8.655(2) A, c = 8.820(2) A, α = 105.42(1)°, β = 89.87(1)°, γ = 107.60(1)°, V = 888 A 3 , and Z = 2; 2 is monoclinic, space group P 2 1 / c , with a = 15.358(4) A, b = 7.304(3) A, c = 17.442(4) A, β = 101.00(2)°, V = 1921 A 3 , and Z = 4.

Structural studies of Fe(III) and Cu(II) complexes of salycylaldehyde benzoyl hydrazone, a synthetic chelating agent exhibiting diverse biological properties

Salicylaldehyde benzoyl hydrazone (SBH) is a Schiff base that can function as a tridentate chelating agent [l-3]. Some thirty years ago, it was shown that this compound has modest bacteriostatic properties when tested in vitro against microorganisms such as Mycobacten’um tuberculosis, Mycobacterium smegmatis, Candida albicans and Aspergillus niger, although these effects were not sufficiently marked to encourage further study at that time [4, 51. Recently, however, interest in the biological properties of SBH has been renewed with the recognrtion that aroylhydrazones of this type are able to induce iron excretion in mammals and thus are potentially of use in the treatment of iron overload on man [6, 71. SBH itself can mobilize iron from iron-loaded reticulocytes in vitro [8] and produces high levels of iron excretion when administered to rats [9] . preliminary studies have also shown that SBH is an unusually potent inhibitor of DNA synthesis in a variety of cultured human and rodent cells and that the complex [CuCl(SBH)]*H,O produces significant inhibition of tumor growth when given to mice bearing a transplanted fibrosarcoma [lo-121. The common mechanism underlying these various biological effects of SBH appears to be an ability to penetrate cell membranes and disrupt the intracellular metabolism of essential metal ions. The exact nature of such disruptions, and the extent to which they may be exploited for therapeutic purposes, require much additional study, including detailed elucidation of the chemical properties of complexes formed between SBH and physiologically-important transition metals. This paper reports single crystal X-ray diffraction studies of two such complexes, [FeCla(SBH)(CHsOH)] and [CuCl(SBH)]~H,O. TABLE I. Selected Bond Distances, in A.

Syntheses and Structures of μ-Oxo-Bis[dichloroiron(III)]-Bis-[2,6-Diacetylpyridinedioximate(-1)]Iron(II) and Related Compounds

The syntheses and structures of four new compounds are described. Two of these compounds are the anhydrous and dihydrate chloride salts of the diamagnetic bis(2,6-diacetylpyridinedioxime)iron(II) cation, [Fe(DAPDH2)2]2+. In this complex cation the DAPDH2 ligand binds to the iron, as expected, through its three nitrogen atoms leaving the four oxime oxygen atoms protonated and uncoordinated. The third compound is (AsPh4)2[Fe2OCl6], a new salt of the well-known oxo-bridged diiron complex, [Fe2OCl6]2−. The synthesis of (AsPh4)2[Fe2OCl6] is a high yield, straightforward, one-step preparation starting with AsPh4Cl and ferrous chloride in methanol. In this synthesis Fe(II) is oxidized to Fe(III) by atmospheric O2. The fourth new compound is the novel and unexpected triiron complex [Fe(DAPDH)2Fe2OCl4]. This complex is derived from [Fe(DAPDH2)2)]2+ and [Fe2OCl6]2− by removing the H+ from each of two adjacent oxime oxygen atoms of the former and one Cl− from each of the Fe(III) ions of the latter. The resulting neu...

The structure of cobalt methylmalonate complexes, CoClN4O7C10H28 and CoCl2N4O5.5C11H28, models for metal complexes of γ-carboxyglutamic acid

Abstract Methylmalonato-2,2′,2″-triaminotriethylaminecobalt(III) chloride was synthesized by two methods, the first involving the addition of 2,2′,2″-triaminotri- ethylamine (tren) to a basic solution of cobalt(II) methylmalonate prepared from methylmalonic acid and cobalt(II) chloride and the second involving the addition of disodium methylmalonate to a solution of [Co(tren)C12] C1·H2O. Crystals of the complex are monoclinic, space group P21/c, a=8.438(2), b = 22.770(7), c = 9.913(3) A, β = 114.6(1)°, Z = 4. The asymmetric unit consists of one complex, a chloride counter ion and three water molecules. A protonated complex was generated in an acidic solution of the first compound and was also characterized crystallographically. The crystals are again monoclinic, space group P21/n, a=9.112(3), b=16.587(4), c= 12.610(4) A, β = 99.32(2)°, Z = 4. In this case, the asymmetric unit contains the complex, two chloride ions, a water molecule and half of an ethanol molecule. A strong hydrogen bond involving one of the carboxylate oxygens not bound to the metal allows the methylmalonate ion to serve as a uninegative, bidentate ligand. This mode of binding suggests a model for how proteins with two adjacent γ-carboxyglutamic acid residues might bind one Ca2+ without causing severe charge balance problems.

The heat of dimerization of acetic acid and the heat of decomposition of ammonium acetate as determined by FTIR spectroscopy

Abstract Using FTIR spectroscopy − (60.3±2.5) kJ·mol −1 has been obtained for the heat of dimerization of gaseous acetic acid and (110±4) kJ·mol −1 has been obtained for the heat of decomposition of solid ammonium acetate into the gases ammonia and acetic acid monomer. The former value agrees well with previous studies where errors due to wall adsorptions were avoided. The value for the decomposition of ammonium acetate is the first to be directly determined by experiment.

Crystal structure of a copper complex of 2-carboxypentonic acid; a decomposition product of dehydroascorbic acid

In acidic aqueous solution and in the presence of copper(II), ascorbic acid is rapidly oxidized to dehydroascorbic acid, which rearranges to give the branched-chain dicarboxylic acid 2-carboxypentonic acid (1,2,3,4-tetrahydroxybutane-1,1-dicarboxylic acid)(H3cpa). The ion cpa3– is sequestered by copper(II) to produce the insoluble crystalline product [Cu9Cl2(cpa)6(H2O)3]2–·xH2O. Characterization of the crystals by X-ray diffraction indicates that copper exists in two distinct environments, one of which is five-co-ordinate and the other six-co-ordinate, and that cpa3– makes seven bonds to copper. Channels of disordered solvent occupy 40% of the cell volume and pass completely through the crystals.