<i>C</i>₁‑Symmetrical Titanium(IV) Complexes of Salan Ligands with Differently Substituted Aromatic Rings: Enhanced Cytotoxic Activity

Diaminobis­(phenolato) (“salan”) titanium­(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>₂-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 IC₅₀ values as low as <1 μM 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

Cytotoxicity and Hydrolysis of <i>trans</i>-Ti(IV) Complexes of Salen Ligands: Structure–Activity Relationship Studies

Eleven bis­(dimethylphenolato) Ti­(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>_1/2 values for labile ligand hydrolysis of 2–11 h in 10% D₂O solutions. In contrast, varying cytotoxicities were achieved, identifying selected members as the first <i>trans</i>-Ti­(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 (IC₅₀ as low as 1.0 ± 0.3 μM), with activity exceeding that of cisplatin by up to 15-fold. Reaction of a representative complex with <i>ortho</i>-catechol yielded a “<i>cis</i>”-Ti­(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 Ti­(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: Structure–Activity Relationship Studies

Eleven bis­(dimethylphenolato) Ti­(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>_1/2 values for labile ligand hydrolysis of 2–11 h in 10% D₂O solutions. In contrast, varying cytotoxicities were achieved, identifying selected members as the first <i>trans</i>-Ti­(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 (IC₅₀ as low as 1.0 ± 0.3 μM), with activity exceeding that of cisplatin by up to 15-fold. Reaction of a representative complex with <i>ortho</i>-catechol yielded a “<i>cis</i>”-Ti­(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 Ti­(IV) complexes, suggesting that the hydrolysis products may also induce cytotoxic effects, thus reducing stability concerns

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 GI₅₀ value of 0.7 ± 0.5 μM, 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

Peptide Models of Cu(I) and Zn(II) Metallochaperones: The Effect of pH on Coordination and Mechanistic Implications

The first NMR structures of Cu­(I) and Zn­(II) peptide complexes as models of metallochaperones were derived with no predetermined binding mode. The cyclic peptide <u>MDC</u>SG<u>C</u>SRPG was reacted with Cu­(I) and Zn­(II) at low and moderate pH. This peptide features the conserved sequence of copper chaperones but with Asp at position 2 as appears in the zinc binding domain of ZntA. The structures were compared with those of the Cu­(I) complexes of the wild-type sequence peptide <u>MTC</u>SG<u>C</u>SRPG. All analyses were conducted first with no metal-binding constraints to ensure accurate binding ligand assignment. Several structures included metal-Met binding, raising a possible role of Met in the metal transport mechanism. Both Cu­(I) and Zn­(II) gave different complexes when reacted with the peptide of the native-like sequence under different pH conditions, raising the possibility of pH-dependent transport mechanisms. Cu­(I) bound the <u>MTC</u>SG<u>C</u>SRPG peptide through one Cys and the Met under acidic conditions and differently under basic conditions; Zn­(II) bound the <u>MDC</u>SG<u>C</u>SRPG peptide through two Cys and the Met residues under acidic conditions and through one Cys and the Met under basic conditions, while Cu­(I) bound the non-native Asp mutant peptide through the Asp and one Cys under both conditions, suggesting that Asp may inhibit pH-dependent binding for Cu­(I). NOESY and ESI-HRMS supported the presence of an aqua ligand for Zn­(II), which likely deprotonated under basic conditions to give a hydroxo group. Coordination similarities were detected among the model system and native proteins, which overall suggest that coordination flexibility is required for the function of metallochaperones

Highly Effective and Hydrolytically Stable Vanadium(V) Amino Phenolato Antitumor Agents

Vanadium­(V) oxo complexes with no labile ligands, including six octahedral complexes with pentadentate diaminotris­(phenolato) ligands and one pentacoordinate complex with a tetradentate aminotris­(phenolato) ligand, were synthesized in high yields. All octahedral complexes demonstrated high hydrolytic stability with no signs of decomposition after days in the presence of water, whereas the pentacoordinate complex decomposed within minutes to release the free ligand, demonstrating the marked impact of coordination number and geometry on the complex electrophilicity. All complexes showed marked cytotoxicity toward human colon HT-29 and ovarian OVCAR-3 cells. In particular, the octahedral complexes exhibited especially high activity, higher than that of cisplatin by up to 200-fold. Selected complexes demonstrated similarly high activity also toward the A2780 and the A2780cis cisplatin-resistant line. High cytotoxicity was also recorded after prolonged incubation in a DMSO solution at 4 and 37 °C temperatures and in biological medium. <i>In vivo</i> studies pointed to high efficacy in reducing tumor size, where no clinical signs of toxicity were detected in the treated mice. These results overall indicate high potential of the tested compounds as antitumor agents