Novel diaroylhydrazine ligands as iron chelators: coordination chemistry and biological activity

The search for orally effective drugs for the treatment of iron overload disorders is an important goal in improving the health of patients suffering diseases such as beta-thalassemia major. Herein, we report the syntheses and characterization of some new members of a series of N-aroyl-N'-picolinoyl hydrazine chelators (the H2IPH analogs). Both 1:1 and 1:2 Fe-III:L complexes were isolated and the crystal structures of Fe(HPPH)Cl-2, Fe(4BBPH)Cl-2, Fe(HAPH)(APH) and Fe(H3BBPH)(3BBPH) were determined (H2PPH=N,N'-bis-picolinoyl hydrazine; H(2)APH=N-4-aminobenzoyl-N'-picolinoyl hydrazine, H(2)3BBPH=N-3-bromobenzoyl-N'-picolinoylhydrazine and H(2)4BBPH=N-(4-bromobenzoyl)-N'-(picolinoyl)hydrazine). In each case, a tridentate N,N,O coordination mode of each chelator with Fe was observed. The Fe-III complexes of these ligands have been synthesized and their structural, spectroscopic and electrochemical characterization are reported. Five of these new chelators, namely H2BPH (N-(benzoyl)-N'-(picolinoyl)hydrazine), H2TPH (N-(2-thienyl)-N'-(picolinoyl)-hydrazine), H2PPH, H(2)3BBPH and H(2)4BBPH, showed high efficacy at mobilizing Fe-59 from cells and inhibiting Fe-59 uptake from the serum Fe transport protein, transferrin (Tf). Indeed, their activity was much greater than that found for the chelator in current clinical use, desferrioxamine (DFO), and similar to that observed for the orally active chelator, pyridoxal isonicotinoyl hydrazone (H2PIH). The ability of the chelators to inhibit Fe-59 uptake could not be accounted for by direct chelation of Fe-59-Tf. The most effective chelators also showed low antiproliferative activity which was similar to or less than that observed with DFO, which is important in terms of their potential use as agents to treat Fe-overload disease.

The preparation and characterization of tin(IV) complexes of 2-quinolinecarboxaldehyde Schiff bases of S-methyl- and S-benzyldithiocarbazates and the X-ray crystal and molecular structures of the 2-quinolinecarboxaldehyde Schiff base of S-benzyldithi

New tin(IV) complexes of empirical formula, Sn(NNS)I-3 (NNS = anionic forms of the 2-quinolinecarboxaldehyde Schiff bases of S-methyl- and S-benzyldithiocarbazate) have been prepared and characterized by a variety of physico-chemical techniques. In the solid state, the Schiff bases exist as the thione tautomer but in solution and in the presence of tin(IV) iodide they convert to the thiol tautomer and coordinate to the tin atom in their deprotonated thiolate forms. The structures of the free ligand, Hqaldsbz and its triiodotin(IV) complex, [Sn(qaldsbz)I-3] have been determined by X-ray diffraction. The complex, [Sn(qaldsbz)I-3] has a distorted octahedral structure with the Schiff base coordinated to the tin atom as a uninegatively charged tridentate chelating agent via the quinoline nitrogen atom, the azomethine nitrogen atom and the thiolate sulfur atom. The three iodo ligands are coordinated meridionally to the tin atom. The distortion from an ideal octahedral geometry of [Sn(qaldsbz)I-3] is attributed to the restricted bite size of the tridentate Schiff base ligand. (C) 2004 Elsevier Ltd. All rights reserved.

Novel one-dimensional structures and solution behaviour of copper(II) bromide and chloride complexes of a new pentapyridyldiamine ligand

Copper(II) bromide and chloride complexes of the new heptadentate ligand 2,6-bis(bis(2-pyridylmethyl)amino)methylpyridine (L) have been prepared. For the bromide complexes, chains of novel, approximately C-2-symmetric, chiral [Cu-2(L)Br-2](2+) 'wedge-shaped' tectons are found. The links between the dicopper tectons and the overall chirality and packing of the chains are dictated by the bromide ion content, not the counter anion. In contrast, the chloride complexes exhibit linked asymmetric [Cu-2(L)Cl-3](+) tectons with distinct N3CuCl2 and N4CuCl2 centres in the solid. The overall structures of the dicopper bromide and chloride units persist in solution irrespective of the halide. The redox chemistry of the various species is also described.

Dimeric allylpalladium(II) complexes with pyrazolate bridges: Synthesis, characterization, structure and thermal behaviour

The synthesis, characterization and thermal behaviour of some new dimeric allylpalladium (II) complexes bridged by pyrazolate ligands are reported. The complexes [Pd(mu-3, 5-R'(2)pz)(eta(3)-CH2C(R)CH2)](2) [R = H; R'= CH(CH3)(2) (1a); R = H, R' = C(CH3)(3) (1b), R = H; R' = CF3 (1c); R = CH3, R' = CH(CH3)(2) (2a); R = CH3, R' = C(CH3)(3) (2b); and R = CH3, R' = CF3 (2c)] have been prepared by the room temperature reaction of [Pd(eta(3)-CH2C(R)CH2)(acac)](acac = acetylacetonate) with 3,5-disubstituted pyrazoles in acetonitrile solution. The complexes have been characterized by NMR (H-1, C-13{H-1}), FT-IR, and elemental analyses. The structure of a representative complex, viz. 2c, has been established by single-crystal X-ray diffraction. The dinuclear molecule features two formally square planar palladium centres which are bridged by two pyrazole ligands and the coordination of each metal centre is completed by allyl substituents. The molecule has non-crystallographic mirror symmetry. Thermogravimetric studies have been carried out to evaluate the thermal stability of these complexes. Most of the complexes thermally decompose in argon atmosphere to give nanocrystals of palladium, which have been characterized by XRD, SEM and TEM. However, complex 2c can be sublimed in vacuo at 2 mbar without decomposition. The equilibrium vapour pressure of 2c has been measured by the Knudsen effusion technique. The vapour pressure of the complex 2c could be expressed by the relation: In (p/Pa)(+/- 0.06) = -18047.3/T + 46.85. The enthalpy and entropy of vapourization are found to be 150.0 +/- 3 kJ mol(-1) and 389.5 +/- 8 J K-1 mol(-1), respectively. (c) 2005 Elsevier B.V. All rights reserved.

Complexes of cytotoxic chelators from the dipyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues

In an effort to better understand the antiproliferative effects of the tridentate hydrazone chelators di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and di-2-pyridyl ketone benzoyl hydrazone (HPKBH), we report the coordination chemistry of these ligands with the divalent metal ions, Mn, Co, Ni, Cu, and Zn. These complexes are compared with their Fe-II analogues which were reported previously. The crystal structures of Co(PKIH)(2), Ni(PKIH)(2), Cu(PKIH)(2), Mn(PKBH)(2), Ni(PKBH)(2), Cu(PKBH)(2), and Zn(PKBH)(2) are reported where similar bis-tridenate coordination modes of the ligands are defined. In pure DMF, all complexes except the Zn-II compounds exhibit metal-centered M-III/II (Mn, Fe, Co, Ni) or M-II/I (Cu) redox processes. All complexes show ligand-centered reductions at low potential. Electrochemistry in a mixed water/DMF solvent only elicited metal-centered responses from the Co and Fe complexes. Remarkably, all complexes show antiproliferative activity against the SK-N-MC neuroepithelioma cell line similar to (HPKIH) or significantly greater than that of the (HPKBH) ligand which suggests a mechanism that does not only involve the redox activity of these complexes. In fact, we suggest that the complexes act as lipophilic transport shuttles that allow entrance to the cell and enable the delivery of both the ligand and metal which act in concert to inhibit proliferation.