Heterocyclic dithiocarbazate iron chelators: Fe coordination chemistry and biological activity

The iron coordination and biological chemistry of a series of heterocyclic dithiocarbazate Schiff base ligands is reported with regard to their activity as Fe chelators for the treatment of Fe overload and also cancer. The ligands are analogous to tridentate heterocyclic hydrazone and thiosemicarbazone chelators we have studied previously which bear NNO and NNS donor sets. The dithiocarbazate Schiff base ligands in this work also are NNS chelators and form stable low spin ferric and ferrous complexes and both have been isolated. In addition an unusual hydroxylated ligand derivative has been identified via an Fe-induced oxidation reaction. X-ray crystallographic and spectroscopic characterisation of these complexes has been carried out and also the electrochemical properties have been investigated. All Fe complexes exhibit totally reversible Fe couples in mixed aqueous solvents at potentials higher than found in analogous thiosemicarbazone Fe complexes. The ability of the dithiocarbazate Schiff base ligands to mobilise Fe from cells and also to prevent Fe uptake from transferrin was examined and all ligands were effective in chelating intracellular Fe relative to known controls such as the clinically important Fe chelator desferrioxamine. The Schiff base ligands derived from 2-pyridinecarbaldehyde were non-toxic to SK-N-MC neuroepithelioma (cancer) cells but those derived from the ketones 2-acetylpyridine and di-2-pyridyl ketone exhibited significant antiproliferative activity

Transition and post-transition metal systems incorporating linked synthetic macrocycles as structural elements

The transition and post-transition metal chemistry of linked macrocyclic ligand systems incorporating all nitrogen as well as mixed-donor sets is reviewed

New heterotopic, linked macrocyclic systems derived from selectively protected macrocycles

The use of orthogonally protected cyclam and 1,9-dithia-5,13-diazacyclohexadecane macrocycles, in combination with aza-18-crown-6, has enabled the efficient synthesis of a new heterotritopic macrocyclic ligand incorporating N4-, N2S2- and NO5-donor sites. A similar strategy has allowed the incorporation of cyclam and 1,9-dithia-5,13-diazacyclohexadecane into a cofacial ligand. Further, the synthesis of novel tetramacrocyclic ligands has been achieved in which the macrocycles are linked in a cyclic arrangement. The availability of different binding sites in the respective products makes the latter suitable candidates for the synthesis of a range of mixed-metal multinuclear complexes

Metal-ion recognition: Selective interaction of silver(I) with tri-linked N2S2 donor macrocycles and their single ring analogues

The interaction of four tri-linked N2S2-donor macrocyclic ligands and their single ring analogues with silver(I) has been investigated. The 3 1 (metal ligand) stoichiometries of the silver(I) complexes of the tri-linked species in dimethyl sulfoxide-d6/CDCl3 were confirmed by means of NMR titrations involving the incremental addition of silver(I) nitrate to the respective ligands in the above solvent mixture and following the corresponding induced shifts in the 1H NMR spectrum. Solid 3 1 (metal ligand) complexes were isolated for each of the parent (unsubstituted) tri-linked ligands. Competitive solvent extraction experiments (water/chloroform) and related bulk membrane transport (water/chloroform/water) experiments have been performed in which each of the four tri-linked ligands as well as their single ring analogues were employed as the extractant/ionophore in the chloroform phase. In both sets of experiments the respective aqueous source phases (buffered at pH 4.9) contained an equimolar mixture of cobalt(II), nickel(II), copper(II), zinc(II), cadmium(II), silver(I) and lead(II) nitrates. For membrane transport the aqueous receiving phase was buffered at pH 3. Under the conditions employed, both the solvent extraction and the bulk membrane transport experiments resulted in high extraction/transport selectivity for silver(I) relative to the other six metal ions present

Synthesis, characterization and X-ray crystal structures of seven-coordinate pentagonal-bipyramidal zinc(II), cadmium(II) and tin(IV) complexes of a pentadentate N3S2 thiosemicarbazone

New complexes of the general formula, [M(Hdap NMetsc)(HO)](NO) ·HO (M = Zn, Cd; H dapNMetsc = 2,6-diacetylpyridinebis(N- methylthiosemicarbazone) and [Sn((dapNMetsc)X] (X = Ph, Cl and I) (dapNMetsc = the doubly deprotonated form of 2,6-diacetylpyridine bis(N-methylthiosemicarbazone) have been synthesized and structurally characterized by a variety of physico-chemical techniques. X-ray crystallographic structure determination shows that in the zinc and cadmium complexes, the bis(thiosemicarbazone) ligand coordinates as a neutral NS pentadentate chelating agent through the two azomethine nitrogen atoms, the pyridine nitrogen atom and the two thione sulfur atoms. The NS donors of the ligand occupy the equatorial plane and the two aqua ligands occupy the sixth and seventh axial positions of the seven-coordinated cadmium(II) and zinc(II) ions. In the tin(IV) complexes, however, the thiosemicarbazone is coordinated to the tin(IV) ion as a dinegatively charged pentadentate chelating agent via the pyridine nitrogen atom, the two azomethine nitrogen atoms and the two thiolate sulfur atoms. The two apical positions of the seven-coordinate tin(IV) ion are occupied by either phenyl, chlorido or iodido ligands. In each of the complexes, the overall geometry adopted by the metal ion may be considered as a distorted pentagonal-bipyramid

New heteroditopic, linked macrocyclic systems derived from selectively protected N2S2-, N3O2- and N4-donor macrocycles\ud

The use of selectively tert-butoxycarbonyl protected derivatives of 1,9-dithia-5,13-diazacyclohexadecane 1, 1,7-dithia-4,11-diazacyclotetradecane 2, 1,4,8,11-tetraazacyclotetradecane 3 and 2,5-dioxa-8,11,14-triaza-1,6(1,2)-dibenzenacyclopentadecaphane 4 has enabled the efficient synthesis of new linked heteroditopic macrocyclic systems incorporating combinations of N₂S₂- and N₄- or N₃O₂-donor sites. Incorporation of two types of binding sites in the respective products makes them suitable candidates for the synthesis of a range of mixed-metal, di- and oligo-nuclear metal complexes

A turn-on fluorescent iron complex and its cellular uptake

Chlorotoxin (CTX), a disulfide-rich peptide from the scorpion Leiurus quinquestriatus, has several promising biopharmaceutical properties, including preferential affinity for certain cancer cells, high serum stability, and cell penetration. These properties underpin its potential for use as a drug design scaffold, especially for the treatment of cancer; indeed, several analogs of CTX have reached clinical trials. Here, we focus on its ability to internalize into cells-a trait associated with a privileged subclass of peptides called cell-penetrating peptides-and whether it can be improved through conservative substitutions. Mutants of CTX were made using solid-phase peptide synthesis and internalization into human cervical carcinoma (HeLa) cells was monitored by fluorescence and confocal microscopy. CTX_M1 (ie, [K15R/K23R]CTX) and CTX_M2 (ie, [K15R/K23R/Y29W]CTX) mutants showed at least a twofold improvement in uptake compared to CTX. We further showed that these mutants internalize into HeLa cells largely via an energy-dependent mechanism. Importantly, the mutants have high stability, remaining intact in serum for over 24\ua0h; thus, retaining the characteristic stability of their parent peptide. Overall, we have shown that simple conservative substitutions can enhance the cellular uptake of CTX, suggesting that such type of mutations might be useful for improving uptake of other peptide toxins

Macrocyclic ligand design: The interaction of selected transition and post-transition metal ions with a 14-membered N2S2-donor macrocycle

Interaction of 1,7-dithia-4,11-diazacyclotetradecane (1) with nickel(II), copper(II) and silver(I) yields the complexes [NiL(H2O)(CH3CN)](ClO4)2, [CuL](ClO4)2 and [AgL]n(ClO4)n (L = 1). The log K values for the 1:1 complexes of cobalt(II), copper(II), zinc(II), cadmium(II), silver(I) and lead(II) in 95% MeOH are reported, with the strongest complexes occurring for copper(II) and silver(I). The X-ray structure of the nickel complex shows the four donors of the macrocycle coordinated around cis positions of an octahedron, with water and acetonitrile ligands occupying the remaining cis positions (the latter are trans to the amine donors and the sulfurs occupy trans axial positions). The silver complex is distorted square pyramidal with all macrocyclic donors bound; each sulfur bridges to an adjacent silver centre such that the latter attains a S3N2 environment and a cationic zig-zag polymeric arrangement is generated

A second generation dendrimer incorporating nine S2N2-donor macrocycles and its palladium(II) complex

A new second generation dendrimer incorporating nine S2N2-donor macrocyclic units that bind nine Pd(II) cations is reported.\ud \ud Interest in the potential applications of nanoscopic structures has fuelled rapid progress in the chemistry of dendrimers and hyperbranched polymers.1 While less studied than purely organic systems, the inclusion of transition metals into such structures is of particular interest as the resulting materials may, for example, display novel magnetic, electronic and/or catalytic properties.2,3 Dendritic structures incorporating macrocyclic ligand units have received less attention.4–7\ud \ud Recently, we have reported metal binding studies8,9 involving the tri-linked N2S2-donor macrocyclic ligands derived from the common precursor 1.10 We now report an extension of these studies in which the linking of nine such rings in a dendritic architecture has been achieved

New linked macrocycle systems. Interaction of palladium(II) and platinum(II) with tri-linked N2S2-donor macrocycles and their single-ring analogues

Palladium(II) and platinum(II) complexes of ligands incorporating three linked, 16-membered, N₂S₂-donor macrocycles, together with their single-ring analogues have been synthesised. The former complexes are of the form [M₃L](PF₆)₆ (where M = Pd or Pt, and L is a linked three-ring macrocyclic species incorporating a 1,3,5-'tribenzyl' or a phloroglucinol core). The X-ray structure determination of the single ring species [PdL](PF₆)₂ (where L is a single N-benzylated derivative of the N₂S₂-donor macrocycle) showed that the palladium is coordinated to all four donor atoms of the macrocycle in a 'square planar' manner. The electrospray mass spectra of the tri-linked metal-containing species show a series of multiply charged ions resulting from the loss of hexafluorophosphate counter ions and hydrogens, and corresponding to [M−nPF₆]ⁿ⁺ and [M−nPF₆−mH]^(n−m)+. Expansion of individual charged peaks revealed the expected wide mass range resulting from the presence of three metal ions, each of which possesses a number of isotopes. Spectrophotometric titrations confirm that 3 ∶ 1 (metal ∶ ligand) stoichiometries occur for the complexes of these tri-linked ligands in acetonitrile