Homoleptic [ONO]2Ti(IV) type complexes of amino-acid-tethered phenolato, Schiff-base ligands: Synthesis, characterization, time-resolved fluorescence spectroscopy, and cytotoxicity against ovarian and colon cancer cells

Six homoleptic Ti(IV) compounds of dianionic tridentate Schiff base ligands were synthesized from chiral amino acids, 2-hydroxybenzaldehyde and Ti(OiPr)4. The compounds were spectroscopically characterized and the molecular geometries were established by X-ray crystallography. The ligands coordinated the titanium via carboxylate-O-, imine-N-, and phenoxide-O atoms. Two isomers were identified; each based on a trans-N2O4 donor set, but one with trans carboxylate-O atoms and another with each carboxylate-O atom trans to a phenoxide-O atom. Photophysical profiles exhibited faster excited-state relaxation in the solid phase than in solution. Marked cytotoxicities were recorded toward human ovarian A2780 and colon HT-29 cancer cells with IC50 values ranging between 23±2 and 103±3 µM. Comparative hydrolytic stability studies by NMR in 10% D2O solutions provided t1/2 values of up to 15±2 h, with little correlation to cytotoxicity implying a role of hydrolysis products in the reactivity and identifying steric bulk as a contributor to stability and solubility

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

NMR characterization of a Cu(I)-bound peptide model of copper metallochaperones: Insights on the role of methionine

The first NMR structure of a Cu(I)-bound metallochaperone model with the conserved sequence MT/HCXXC revealed that at pH 3.0 and 6.8 Cu(I) binds through one Cys and the Met rather than the two Cys residues, differently than at pH 8.5. This suggests a possible role of Met in metal transport