28 research outputs found
Cytotoxicity and Hydrolysis of <i>trans</i>-Ti(IV) Complexes of Salen Ligands: StructureāActivity Relationship Studies
Eleven bisĀ(dimethylphenolato) TiĀ(IV) complexes of salen
ligands
with different steric and electronic properties due to different aromatic
substituents at the ortho and para positions are reported, and their
cytotoxicity toward HT-29 and OVCAR-1 cells and its dependence on
hydrolytic behavior are discussed. Eight complexes of this series
were analyzed by X-ray crystallography, confirming the trans geometry
of the labile ligands with otherwise relatively similar coordination
features to those of <i>cis</i>-salan analogues. Relatively
high and similar hydrolytic stability is observed for all complexes,
with <i>t</i><sub>1/2</sub> values for labile ligand hydrolysis
of 2ā11 h in 10% D<sub>2</sub>O solutions. In contrast, varying
cytotoxicities were achieved, identifying selected members as the
first <i>trans</i>-TiĀ(IV) complexes reported as anticancer
agents. Steric bulk all around the complex diminished the activity,
where a complex with no aromatic substitutions is especially active
and complexes substituted particularly at the ortho positions are
mostly inactive, including <i>ortho</i>-halogenated and <i>ortho</i>-<i>tert</i>-butylated, with one exception
of the <i>ortho</i>-methoxylated complex demonstrating appreciable
activity. In contrast, <i>para</i>-halogenation provided
the complexes of highest cytotoxic activity in this series (IC<sub>50</sub> as low as 1.0 Ā± 0.3 Ī¼M), with activity exceeding
that of cisplatin by up to 15-fold. Reaction of a representative complex
with <i>ortho</i>-catechol yielded a ā<i>cis</i>ā-TiĀ(IV) complex following rearrangement of the salen ligand
on the metal center, with highly similar coordination features and
geometry to those of the catecholato salan analogues, suggesting that
the complexes operate by similar mechanisms and rearrangement of the
salen ligand may occur upon introduction of a suitable chelating target.
In additional cytotoxicity measurements, a salen complex was preincubated
in the biological medium for varying periods prior to cell addition,
revealing that marked cytotoxicity of the salen complex is retained
for longer preincubation periods relative to known TiĀ(IV) complexes,
suggesting that the hydrolysis products may also induce cytotoxic
effects, thus reducing stability concerns
Cytotoxicity and Hydrolysis of <i>trans</i>-Ti(IV) Complexes of Salen Ligands: StructureāActivity Relationship Studies
Eleven bisĀ(dimethylphenolato) TiĀ(IV) complexes of salen
ligands
with different steric and electronic properties due to different aromatic
substituents at the ortho and para positions are reported, and their
cytotoxicity toward HT-29 and OVCAR-1 cells and its dependence on
hydrolytic behavior are discussed. Eight complexes of this series
were analyzed by X-ray crystallography, confirming the trans geometry
of the labile ligands with otherwise relatively similar coordination
features to those of <i>cis</i>-salan analogues. Relatively
high and similar hydrolytic stability is observed for all complexes,
with <i>t</i><sub>1/2</sub> values for labile ligand hydrolysis
of 2ā11 h in 10% D<sub>2</sub>O solutions. In contrast, varying
cytotoxicities were achieved, identifying selected members as the
first <i>trans</i>-TiĀ(IV) complexes reported as anticancer
agents. Steric bulk all around the complex diminished the activity,
where a complex with no aromatic substitutions is especially active
and complexes substituted particularly at the ortho positions are
mostly inactive, including <i>ortho</i>-halogenated and <i>ortho</i>-<i>tert</i>-butylated, with one exception
of the <i>ortho</i>-methoxylated complex demonstrating appreciable
activity. In contrast, <i>para</i>-halogenation provided
the complexes of highest cytotoxic activity in this series (IC<sub>50</sub> as low as 1.0 Ā± 0.3 Ī¼M), with activity exceeding
that of cisplatin by up to 15-fold. Reaction of a representative complex
with <i>ortho</i>-catechol yielded a ā<i>cis</i>ā-TiĀ(IV) complex following rearrangement of the salen ligand
on the metal center, with highly similar coordination features and
geometry to those of the catecholato salan analogues, suggesting that
the complexes operate by similar mechanisms and rearrangement of the
salen ligand may occur upon introduction of a suitable chelating target.
In additional cytotoxicity measurements, a salen complex was preincubated
in the biological medium for varying periods prior to cell addition,
revealing that marked cytotoxicity of the salen complex is retained
for longer preincubation periods relative to known TiĀ(IV) complexes,
suggesting that the hydrolysis products may also induce cytotoxic
effects, thus reducing stability concerns
<i>C</i><sub>1</sub>āSymmetrical Titanium(IV) Complexes of Salan Ligands with Differently Substituted Aromatic Rings: Enhanced Cytotoxic Activity
DiaminobisĀ(phenolato)
(āsalanā) titaniumĀ(IV) complexes
of differently substituted aromatic rings were synthesized, and their
hydrolytic stability and cytotoxicity were analyzed and compared to
those of the <i>C</i><sub>2</sub>-symmertrical analogues
and their equimolar mixtures. The hydrolytic stability of the asymmetrical
complexes was in between those of the symmetrical analogues, implying
an additive influence of the ligand structural parameters. Most mixed
halogenated/nitrated complexes showed a marked improvement of cytotoxic
activity relative to the symmetrical analogues and their mixtures,
with IC<sub>50</sub> values as low as <1 Ī¼M corresponding
to activity exceeding that of cisplatin by up to 30-fold. In contrast,
asymmetrical complexes with substitutions of similar properties revealed
an added influence of both, with cytotoxicity in between those of
the symmetrical analogues. With the presumption that the active species
is generally a polynuclear hydrolysis product kept in mind, it is
overall evident that particular ligand design and fine-tuning of the
parameters of influence including hydrophilicity and hydrophobicity
are essential for maximizing biological efficiency
Anticancer diaminotris(phenolato) vanadium(V) complexes: Ligand-metal interplay
<p>Vanadium complexes are attractive candidates for anticancer chemotherapy, although often suffering from rich aqueous chemistry and hydrolytic instability. We have introduced an LVO family of vanadium oxo complexes, L being a diaminotris(phenolato) chlelating ligand, demonstrating high hydrolytic stability in water along with promising <i>in vitro</i> and <i>in vivo</i> efficacy. Herein we analyzed mechanistic aspects of the reactivity of such complexes in cellular environment. A representative complex exhibited high activity toward all lines in the NIH NCI-60 panel, with an average GI<sub>50</sub> value of 0.7Ā Ā±Ā 0.5Ā Ī¼M, and with a unique reactivity pattern implying a distinct mechanism. Free ligands demonstrated cytotoxicity similar to that of their vanadium complexes, were identified in cells treated with the complex, and induced apoptosis as did the parent complex, all implying their participation as active species. Cell cycle studies pointed to possible arrest mostly at the S phase, with some variations for the complex and ligand on the two lines analyzed. Nevertheless, the vanadium ion apparently accelerated cellular entry, as the activity was evident following markedly shorter periods of incubation with the extracellular complex when compared with the free ligand. The results displayed herein overall highlight the role of the vanadium complex as a pro-drug.</p