|dc.description.abstract||The aims of this work were first to synthesize and fully characterize compounds that may
function as bleomycin analogues and, second, to test their anticancer activity in vitro. Three
novel tetradentate O,N,N,O Schiff base ligands, H₃L¹, H₂L³ and H₂L³ were synthesized by
condensation of three different 1,3-diaminoalkane bridging units with two equivalents of
(2,4-dihydroxy–phenyl)-(phenyl)methanone. These ligands contain two neutral imine
nitrogen donors and two anionic phenolate oxygen donors for the coordination of metal ions.
The choice of ligand was guided by the fact that Cu(II) bleomycin analogues with ligands
employing O,N,N,O donor atom sets are able to cleave double-stranded DNA via oxygen
radical formation. Using these ligands, six novel metal complexes of copper(II), nickel(II)
and zinc(II) were synthesized and fully characterised. Two novel ligand crystal structures and
six novel metal complex crystal structures are reported in this work.
The X-ray structures of the two structurally characterized nickel(II) complexes [Ni(L²)] and
[Ni(L³)] adopted the same nominally square planar coordination geometry, with the metal ion
bound by the pairs of imine nitrogen and ortho-phenolic oxygen atoms of the ligand’s
tetradentate donor atom set. The Ni–N and Ni–O distances averaged 1.892(3) Å and
1.845(2) Å, respectively. However, when reacted with Cu(II) and Zn(II), the ligands favored
the formation of multinuclear complexes as a result of metal ion bridging by ionized oxygen
donor atoms (either the phenolic oxygen atoms or an alkoxide oxygen atom of the 2-hydroxy
substituted alkane bridge in the case of H₃L¹) of the polyfunctional ligands. For the di- and
trinuclear copper(II) complexes, the mean Cu–N and Cu–O distances averaged 1.953(3) Å
and 2.082(3) Å, respectively. For the dinuclear zinc(II) complex, the mean Zn–N and Zn–O
distances averaged 2.074(3) Å and 2.042(3) Å, respectively.
Electron spin resonance (ESR) measurements on the paramagnetic trinuclear copper(II)
complexes confirmed that the trinuclear solid state structures remain intact in fluid solution
(DMF) and that two of the three copper(II) ions are antiferromagnetically coupled, leaving
the third as an S = ½ center with a hyperfine coupling constant to the I = 3/2 Cu nucleus of
14.80 G. Super-hyperfine coupling (15.13 G) to two N atoms was also evident, consistent with one of the terminal copper(II) centers (O,N,N,O donor atom set) being the site of the unpaired spin density in the molecule.
Density functional theory (DFT) simulations were used to determine the electronic structures of the diamagnetic mononuclear nickel(II) complexes. The simulations reproduced the structures of [Ni(L²)] and [Ni(L³)] accurately with similarity coefficients for the two complexes of 0.982 and 0.990, respectively. The simulated electronic spectra (TD-DFT) of
the nickel(II) complexes showed reasonably good agreement with the experimental spectra and were useful for the assignment of the low-lying MLCT state (near 400 nm) for the complexes as well as the higher-lying π-π* transitions between 300–350 nm. All of the metal complexes and one ligand were sent to MINTEK¹ (Project AuTEK) for anticancer screening. The copper(II) complexes (bleomycin analogues capable of generating
hydroxyl radicals in vivo) showed significant cytotoxicity against the human cancer cell lines A549, DU145, HT-29, and U21. The trinuclear complexes were the most cytotoxic with mean IC₅₀ values of 6(2) and 7(1) μM for [Cu₃(L²)₂Cl₂(DMF)₂] and [Cu₃(L³)₂(H₂O)₂]Cl₂, respectively. The nickel(II) complexes [Ni(L²)] and [Ni(L³)] were comparatively inactive
with mean IC₅₀ values of >50 and 35(16) μM, respectively, consistent with the fact that they do not readily generate reactive oxygen species in a cellular environment.||en