Physicochemical and structural studies on two tridentate antitumour ligand systems : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in chemistry at Massey University
This work is an investigation into the physicochemical and structural properties of two
tridentate, antitumour ligand systems and is divided into two sections. In the first (Chapters 1
to 4), the ligand 2-formylpyridine thiosemicarbazone (LH - containing an NNS donor set),
several of its congeners and a range of complexes (predominantly Cu(II)) were prepared. The
second section (Chapters 5 and 6) deals with a range of ligands based on salicylaldehyde
benzoylhydrazone (sbH2 - containing an ONO donor set), their complexes (predominantly
Cu(II)) and the cytotoxicity data for all of this work.
In Chapter 1 , complexes of the general formulation [CuLX]2 for the deprotonated and
[Cu (LH)XhX2 for the neutral, protonated ligand were prepared (where X = e.g. halide,
pseudohalide, NOj, Cl04, CH3COO-, CF3COO-). The complexes formed are very stable in
strong, non-oxidising acid solutions and with roildly reducing anions, but are susceptible to
oxidising acids and anions. The crystal structures of the neutral ligand, dimeric, one-atom
anion bridged complex [Cu(LH)(CF3C00)]2(CF3C00)2 and the monomeric complex
[Cu(LH)(Cl04hH20}2H20 with axially coordinated perchlorato groups were determined.
In Chapter 2, the possibility that in vivo S and N donor atom adducts of CuL + may form was
investigated in vitro. Stable complexes containing a copper(II)-thiolato bond were isolated at
ambient temperatures, under aerobic conditions. The e.s.r. parameters for these were very
similar to a species formed from the interaction of CuL + with human blood components.
Ternary, Lewis-base adducts of nitrogen donor atoms were also isolated, and the crystal
structures for two of these, [CuL(2,2'-bipyridyl)]Cl04 and [CuL(saccharinato)H20J·Y2H20,
The possibility of CuL + interacting with 0 donor groups (in particular phosphates) in vivo was
investigated in vitro in Chapter 3. The ternary complexes isolated contain the anions monoiv
and dihydrogenphosphate, pyrophosphate, phenolate and molybdate. The crystal structure of
[Cu(LH)(H2P04)h(H2P04)2(H3P04h·2H20 showed the complex is dimeric, having a unique
one-atom dihydrogenphosphate bridge, three inequivalent phosphates and a very strong
interphosphate hydrogen-bond. In contrast, the ternary, pyrophosphate complex
[(CuL)4P207} l2H20 is a tetramer, with each Cu(II) centre having a one-atom S, a three-atom
pyrophosphate and two five-atom pyrophosphate bridges.
The low temperature magnetic properties of [CuL(CH3 C00)]2 fit the Bleany-Bowers
expression well, whereas for [(CuL)4P207} l2H20 a very weak interaction through the fiveatom
pyrophosphate bridge may account for the non-dimeric behaviour observed. Both
complexes are weakly antiferromagnetic (-2J -6 cm-1).
In Chapter 4, four variations on the ligand LH and a representative series of their Cu(II)
complexes were synthesised. Reduction potentials for a Cu(II) complex of each ligand, as well
as for two thiolato and a Lewis-base adduct of CuL +, were measured. N.m.r. spectroscopy
was used to characterise the ligands and pKa values for both the ligands and their Cu(II)
complexes were determined. No correlation between any of these values and the cytotoxicities
In Chapter 5, Section 2, a range of ligands based on sbH2 (salicylaldehyde benzoylhydrazone)
and their transition metal complexes (predominantly Cu(II)) were synthesised for cytotoxicity
trials (on the cell line HCT-8). A number of the Cu(II) complexes had depressed room
temperature magnetic moments and displayed e.s.r. spectral features which were attributed to
magnetic interactions in the solid state. The crystal structure of [Cu(sbH)Cl04(EtOH)]2
revealed it to be a planar, side-by-side dimer with Cu(sbH)+ moieties bridged via the
Depending upon the pH, sbH2 can coordinate as either a neutral, monoanionic or dianionic
moiety to transition metals. The interaction of CuF2.2H20 in HF with sbH2 resulted in the in
situ formation of H2 S i F 6 . The crystal structure of the resulting complex,
[(Cu(sbH)H20hSiF6}2H20, showed it to be a dimer, with the Cu(II) centres linked by the
coordinated SiFg- anion. The crystal structure of a cytotoxically inactive Cu(sbH)+ analogue,
[Cu(saH)Cl(H20)]H20 was also solved.
In the final chapter, the cytotoxicity data for all compounds tested are presented. The
copper(II) complexes generally showed activities different to the metal free ligands. For LH
congeners the complexes were no better than the ligands; in contrast to the sbH2 analogues
where the Cu(II) chelates were statistically more cytotoxic. Transition metals other than Cu(II)
either did not improve the activity or resulted in a reduction or loss of cytotoxicity.
For LH congeners, changes in cytotoxicity could be related to altered electronic and steric
properties, whereas for the sbH2 series of compounds, statistical analysis showed the
lipophilicity conferred by a substituent to be the dominant factor. Comparisons with proven
anticancer drugs are made and possible future studies to maximise the biological activity are
suggested. All of the compounds tested for their antiviral activity were either cytotoxic or
inactive at the concentrations used.